2018 MEDICARE CODING UPDATE P. 19 • TORIC ALIGNMENT TECH P. 22 SUPPLEMENTS AND GLAUCOMA P. 40 • GORE-TEX SUTURING TRICKS P. 47 A REVIEW OF POSTERIOR SCLERITIS P. 50 • PEDIATRIC OCULAR ONCOLOGY P. 55 Review of Ophthalmology Vol. XXV, No. 2 • February 2018 • Presbyopic Inlays • Breakdown Corneal of SMILE • • Toric Manual LRIs Alignment

FebruaryFebruary 20182018

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• Can Corneal Inlays Work fforor YouYou?? P. 26 • Breaking Down the SMILE ProceProceduredure P. 3322 • Is There Still a Place for MaManualnual LRILRIs?s? P. 36

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RP1017_Alcon Systane.indd 1 9/15/17 10:25 AM REVIEW NEWS Volume XXV • No. 2 • February 2018 Research Highlights from The Latest OIS Meeting

Just before this year’s annual American says. “In the study, it was suggested the Graybug Vision implants should, Academy of Ophthalmology meeting, that a higher proportion of patients theoretically, inhibit all isoforms over ophthalmologists and industry leaders can go to a less-frequent, 12-week dos- six months or more.” got together at the Ophthalmology ing schedule.” • Opthea presented evidence of Innovation Summit to discuss the • The company PanOptica is also add-on or combination effi cacy with status of various nascent drugs, developing a topical AMD treatment, their anti-VEGF C/D TRAP-like devices and ophthalmic companies, a small-molecule tyrosine kinase in- molecule. “Interestingly,” notes Dr. with an eye toward their current or hibitor that has shown an effect. “We Cunningham, “they showed that they future fi nancial performance. Review currently have very effective therapies could get regression of the neovascu- caught up with OIS co-chair Emmett in the form of intravitreal injections,” larization in half of the patients that T. Cunningham Jr, MD, PhD, MPH, Dr. Cunningham says, “so there is a were treated in the current study.” for his take on the highlights of the high threshold for effi cacy. This always • Iconic Therapeutics is work- ophthalmic pipeline. makes for a high hurdle for something ing on a tissue-factor inhibitor for In the retina realm, several products that’s not administered in the eye, but wet AMD, ICON-1, that has shown generated buzz: rather is delivered topically.” an ability to reduce retinal thickness • This fall, Spark Therapeutics’ • Genentech is continuing its LAD- and perhaps result in a more durable gene therapy for inherited blindness, DER trial for extended-release ranibi- effect when used in combination with Luxturna, received a unanimous vote zumab. “It involves a surgical proce- ranibizumab. “ICON-1 is an anti- for approval by the FDA review panel, dure to implant the device needed to tissue-factor fusion protein that has and followed this up with a Decem- achieve extended release,” Dr. Cun- a unique target,” Dr. Cunningham ber approval. “I think Spark’s Phase ningham explains. “The intention with explains. “They showed that, when it III data was, in a word, tremendous,” extended release is to decrease the was added to ranibizumab, there was Dr. Cunningham says. “This is the fi rst frequency of injections from monthly more drying than with ranibizumab gene therapy we’ve seen approved in to every three or four months, or even alone, though it was a small trial. The ophthalmology, and there’s a clear ef- less frequently. It will be interesting to vision didn’t change with the combina- fi cacy benefi t.” Dr. Cunningham notes see how much extended-release ability tion, however. I believe they plan to do that gene-therapy trials coming up be- LADDER shows.” a confi rmatory Phase II trial.” hind Luxturna include GenSight’s trial • The pharmaceutical company • Allegro is working on an anti- for Leber’s Congenital Optic Neurop- Graybug Vision has been studying its integrin inhibitor as a treatment for athy, AGTC’s trials in X-linked retinos- six-month, time-release delivery of the diabetic retinopathy that, according chisis and achromatopsia; Nightstar’s small molecule sunitinib for wet AMD to a post-hoc analysis of the Phase II trial for choroideremia; and Regenx- in animal models. Dr. Cunningham, data, may have enhanced effi cacy in bio’s trial in wet AMD. who is an investor in Graybug, says patients who are incomplete respond- • Novartis’ brolucizumab, a small, that, if the approach works, it could ers to anti-VEGF drugs. “There ap- single-chain variable antibody frag- be a broad inhibitor of the factors that pears to be a clear drug effect.” Dr. ment, was shown to be noninferior to promote AMD. “The current anti- Cunningham says. “You can see some afl ibercept (Eylea, Regeneron), for the VEGF agents are all targeting VEGF drying. And, as monotherapy, it seems treatment of wet age-related macular isoform A,” Dr. Cunningham explains. to be an improvement vs. anti-VEGF. degeneration. “So, it looks like we’ll “But there are other isoforms—par- However, now they’re trying to fi gure have a fourth competitor coming to ticularly C and D—that also appear the way forward: Do they treat non- the AMD market,” Dr. Cunningham to be important. The sunitinib that responders? All patients? They haven’t (Continued on p. 8)

February 2018 | reviewofophthalmology.com | 3

0003_rp0218_news.indd03_rp0218_news.indd 3 11/26/18/26/18 2:552:55 PMPM Ophthalmic Product Development Insights Aki Tobaru, Hiro Matsuda, PhD, & Matthew Chapin • Ora Inc., Andover, Mass. REVIEW Matthew Chapin and Hal Patterson • Andover, Mass.

Nonclinical Considerations: Focus on Chemistry, Manufacturing and Controls

n this installment of Ophthalmic Product approaches to container closure: multi- formulation for GLP ocular toxicology that’s Development Insights, we’ll review dose, three-part systems (bottle, tip, cap); similar to—or, optimally, the same as—that Iconsiderations for early-stage develop- blow-fi ll seal (BFS; typically unit dose and used in your intended clinical study. In many ment of a new product as the entrepreneur preservative-free); and tubes, which are cases, formulation and scale-up are the charts his path to the fi rst clinical trial. Most generally used for ointments. Other novel rate-limiting factors in ophthalmic product of the prior columns have emphasized that systems like multidose, preservative-free development, so setting your formulation having the target-product profi le drafted bottles; or dual-chamber containers that early and then locking it in for the trials is and defi ned early is critical to under- allow drug components to be separate until important. standing key elements that contribute to mixing before use, are available for consid- If changes to the formulation are neces- designing a proper clinical development eration but are more complex solutions that sary as you proceed through your nonclinical strategy. In this article, we’ll specifi cally often aren’t used in early trials due to their program, you need to consider whether look at issues around CMC (Chemistry, time and cost requirements, which can be you can demonstrate to the FDA that those Manufacturing and Controls), an area that’s prohibitive for startup companies. In those changes don’t impact safety or penetration often outside the expertise and experience cases, alternatives for use in the early trials of the drug into the ocular tissues. Adding a should be considered. In some situations of the entrepreneur ophthalmologist. Proper demulcent, for example, while a seemingly benign addition, can increase dwell time of CMC planning requires a basic understand- the drug on the surface of the eye and ing of the various interdependent thus, theoretically, drug penetra- steps of development: the design tion. Don’t underestimate the of the fi rst clinical trial and implications of formulation of the toxicology studies; a changes as you near investi- preliminary idea of the com- gational new drug status with mercial container closure; the FDA. It goes without saying formulations; clinical dosing; that you want to avoid having to pharmacokinetic consider- repeat GLP ocular toxicology. ations; and other components. Another aspect of formulation you All of these factors infl uence the don’t want to underestimate is the CMC strategy. addition of the preservative, which is We aren’t able to exhaustively review usually required for multidose containers. all of the critical requirements for CMC here, While, again, simply adding a preservative but we can offer a few pearls we’ve picked in which a unit-dose blow-fi ll seal doesn’t may be considered a benign change, it’s the up after taking part in many development fi t the timeframe/cost of the early program, type of change that requires a confi rmation projects. We hope these pearls are useful, small multidose containers can be used as of stability as an early part of your plan, and pertinent to the issues the entrepreneur/ single-dose units in initial studies. But we’ve since there have been cases in which a fi rst time startup company will encounter. also learned that headspace inside the bottle preservative ends up compromising a drug’s (the empty space inside the bottle between stability. Also, excipients have been shown Container Closure the top of the bottle and the drug inside) to interact with preservatives. Therefore it’s Locally administered ophthalmic products may be critical for a specifi c drug, and that a good idea to perform a standard preserva- are required to be sterile and in a container scaling up the process to BFS later may tive effectiveness test (PET) early on as you closure system that prevents contamination. highlight new issues when you’re trying to work through formulation development, to This alone can cause unique issues, but also start Phase III (e.g., problems with the heat avoid surprises that require you to make presents multiple options for proceeding in involved in the BFS processing). Therefore, adjustments. If adjustments are required some cases. one needs to keep in mind the potential risks after learning that an excipient impacts The closure system you use in your early associated with any anticipated changes to preservative activity, as mentioned earlier, trials may not be the one you ultimately container closure down the road. Ultimately, there’s a risk that you’ll need to repeat at settle on for commercial use. It helps, it’s a business decision that balances time, least some bridging toxicology. These cases however, to understand your end goal so cost and risk. may not require a full toxicology study, but that you can understand the overall strategy only a streamlined study that bridges to ear- as you progress from early to later stages Formulations and Stability lier toxicology studies. Properly sequencing of development, and set expectations about As you plan your toxicology studies (per these steps is paramount. Even if supplies requirements that may be involved at each Good Laboratory Practices standards), it don’t use the fi nal manufacturing process, step. This includes anticipating technol- can be useful to know that the laboratory as long as toxicology is conducted with a ogy transfer, or shifting from one source can take aliquots from bulk drug containers. formulation that doesn’t have a cleaner or manufacturer to another, that may be (There’s no specifi c requirement to use your impurity profi le than the intended clinical required between Phases II and III. In intended clinical container closure system at formulation, you’ll have appropriate toxicol- ophthalmology, there are a few standard this stage.) However, it’s important to use a ogy coverage.

4 | Review of Ophthalmology | February 2018

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RP0118_Keeler Slit.indd 1 12/19/17 3:39 PM Ophthalmic Product Development Insights Aki Tobaru, Hiro Matsuda, PhD, & Matthew Chapin • Ora Inc., Andover, Mass. REVIEW Matthew Chapin and Hal Patterson • Andover, Mass.

GLP requirements state that the trial inves- don’t have full control of your process, set- be able to demonstrate competence in these tigator needs to confi rm activity and stability ting aside other concerns around what dose SOPs when you attempt to fi nd a partner to during the course of the study. This of course is being delivered to different patients. For help develop the product, since it shows that relates to the timing of when stability-indicat- drugs, don’t simply plan that overages can you’ve maintained the proper level of over- ing assays are available for the active drug solve stability issues. sight and controls. As a sponsor, for example, in your specifi c formulation. This all relates There are nuances that are indication- to the duration of the planned clinical trial. As specifi c, e.g., such as those for dry eye. vendor qualifi cations (before any work is a side note specifi c to biologicals, as part of Excipients that are already approved as done) and audits should be part of your plan. the release testing of clinical supplies prior monograph demulcents (see 21 C.F.R. 349), Don’t ignore the quality oversight required to the study, the FDA likes to see that drug may lead to issues in the clinical/regulatory for complying with GLP (Good Laboratory activity is also measured in an assay that is path with FDA, because those excipients in Practices) and GMP (Good Manufacturing pertinent to the mechanism of action of the effect are already accepted to be used in dry Practices) regulations. drug. The release of clinical supplies refers eye as tear substitutes. This may lead to the to the testing that measures the amount of FDA considering your drug a combination In Conclusion the active drug, and also includes tests of product. Therefore, if you’re going after dry The path for CMC leading to IND and pH and osmolarity, all of which have to meet eye as an indication, your best bet is to make predefi ned specifi cations prior to using a sure you don’t have HPMC, CMC, PVA, etc., starting the fi rst trial requires knowledge drug product in a trial. Therefore, setting up in monograph-level ranges early on in your and expertise (or access to it) in the areas the appropriate assays early in the process formulation unless they’re needed and you of formulations, GMP, sterile manufactur- is important. Lastly, as another side note, anticipate having a proper clinical-regulatory ing, microbiology and others. It’s critical remember that the toxicology for a biological strategy accounting for this. This has been an to understand how the CMC components agent needs to be done in a species in which issue in some projects that were thought to tie into toxicology, regulatory and clinical activity is also confi rmed. need a surfactant or demulcent for stability or concerns, and shouldn’t be viewed in isola- Another pearl on the sequencing of comfort, or one of these agents was part of a tion. A cross-disciplinary approach is needed CMC centers on how to best leverage the product profi le early on, and led to delays in to avoid delays or repeating activities later. engineering batch. This is usually a batch reformulation or unexpectedly increased the manufactured using the same intended complexity of a clinical program. This holistic view also feeds into formulating process and formulation as the clinical proper questions for pre-IND meetings and batch, but at smaller batch size. While not a Sterilization’s Impact anticipating any specifi c issues your program regulatory requirement per se, this batch can Ophthalmic products need to be sterile, might run into early on, so you can avoid be used to supply the GLP toxicology study and indeed most ophthalmic products are multiple meetings with the FDA, if possible and also to show stability for the intended sterile-fi ltered. This highlights the importance (though multiple meetings are acceptable clinical batches. We have seen clients who, of ensuring that the drug product can be and a separate CMC meeting with the FDA as they scale up from, for example, early lab- fi ltered with fi lter validation studies early in isn’t uncommon). pharmacy-compounded drugs to full GMP the process. While an option, it’s best not to manufacturing of drugs, fi nd unexpected have to resort to other methods like heat, We’ll conclude with the theme that runs issues that take more time to solve. While e-beam or ethylene oxide for early work. through all of these columns: Always keep engineering batches are standard and may Thicker products may have issues with the end goal in mind, and develop a properly seem an obvious step, make sure the timing standard fi ltering. Generally, these issues can defi ned target product profi le early on. When is built in up front not only for the engineer- be solved by methodically working through you begin, it’s critical to focus on building a ing batches themselves but for timing and them, but don’t underestimate the potential multidisciplinary strategy and timeline of all work involved in developing the process. for fi ltration problems. Ointments can create activity in order to identify interdependent Demonstration of stability of the intended cost and time delays because many manu- and/or rate-limiting steps and to effectively concentrations of the drug is required for the facturers that make ointments, such as those conduct the product-development orchestra. entire length of the clinical trial. (Note that made for dermatological applications, aren’t this, of course, includes the start-up time necessarily set up to be sterile. Keep in mind of the trial and full time that drug will be at the time it takes to defi ne manufacturing site Mr. Chapin is senior vice president of sites, not just how long a single patient is options if you’re going after approval for an corporate development at the ophthalmic enrolled). Your early engineering batches can ophthalmic ointment. consulting and development fi rm Ora, and Mr. serve as support for this, so that once clinical Patterson is vice president of quality. batches are manufactured and labeled they Quality Systems Ora provides development, clinical-regula- can be used in the trial. One fi nal note: As the sponsor, the ultimate tory and consulting services for developers, Another point in manufacturing and testing: responsibility for the project and for your investors and pharmaceutical companies. If you expect that your drug product will have vendors lies with you. In order to prop- The authors welcome your comments or a drop in stability during processing (e.g., erly demonstrate sponsor oversight, even down to 80 percent), you might wonder if you if you’re a virtual company and plan to questions regarding product development. can just plan to manufacture at 120 percent outsource all the work, you need to establish Please send correspondence to mchapin@ so as it degrades it winds up at 100. This is a basic system of standard operating oraclinical.com or hpatterson@oraclinical. not acceptable, because it implies that you procedures to ensure quality. It also helps to com, or visit oraclinical.com.

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RP1017_Akorn Consumer.indd 1 9/20/17 9:55 AM REVIEW News (Continued from p. 3) communicated their plan publicly yet.” Phase 2b study, codenamed TIME-2b. 10 µg and 15 µg, administered every 16 • Another company working on • In the dry-AMD realm, Apellis weeks —to daily timolol drops. a diabetic retinopathy treatment is Pharmaceuticals recently shared posi- • Taking a different approach to Clearside Biomedical. In a group of tive results from a Phase II trial of its glaucoma and macular telangiecta- patients with diabetic macular edema complement inhibitor. Specifi cally, it sia treatment, Neurotech is pursu- in the company’s HULK explorato- inhibits complement-3. (Complement ing encapsulated cell therapy with a ry clinical trial, Clearside’s CLS-TA is believed to contribute to the patho- therapy designated NT-501. In ECT, showed some positive results. CLS-TA genesis of AMD.) “This development an implanted device releases ciliary is a proprietary suspension formula- is fascinating because we’ve had mul- neurotrophic factor over time, and Dr. tion of triamcinolone acetonide that’s tiple failures of complement inhibitors, Cunningham says the company has administered suprachoroidally with or such as eculizumab (which targeted Phase I/II data that appear to show a without intravitreally injected afl iber- C5) and lampalizumab (which tar- drug effect. “The issue with that plat- cept. In HULK, more than two-thirds geted Factor D),” Dr. Cunningham form is the manufacturing complexity,” of eyes achieved greater than 50 per- muses. “But then Apellis comes with he explains. “This isn’t like synthesiz- cent reduction in excess central reti- anti-C3 showing a benefi t in Phase ing a small molecule and putting it in nal thickness and there was anatomic II. However lampalizumab showed a a bottle that has a two-year shelf life. improvement in all of the treated eyes. benefi t in Phase II also, reinforcing the It’s a device with encapsulated cells.” A The company will soon report results idea that Phase II doesn’t always pre- recent communiqué from Neurotech of a randomized trial in noninfectious dict Phase III success. This raises the announced positive Phase II results in posterior uveitis and has ongoing trials question: Why would C5 inhibitors fail macular telangiectasia, and it’s expect- in retinal vein occlusion and diabetic but a C3 inhibitor work? Many of the ed that a Phase III trial is on its way. macular edema. diagrams we see that illustrate comple- • In the uveitis arena, Dr. Cun- • Drug company Aerpio is also an- ment inhibition show a path that goes ningham says that both pSivida and gling to enter the diabetic retinopathy through C3 and then to a C5-mediated Clearside Biomedical are using sus- space with its twice-daily subcutane- membrane attack complex. However, tained-release corticosteroids and have ous injection of AKB-9778, a small- an equally valid depiction has three produced some very promising results. molecule inhibitor of VE-PTP, which it effector arms, not just one: The other In pSivida’s case, in a six-month study describes as a critical regulator of Tie2 two are chemotaxis—or bringing im- of the Durasert implant in uveitis con- in diseased blood vessels. The idea mune cells and promoting adaptive ducted in India, 22 percent of patients is to restore healthy Tie2 activity. “It immunity so the body can learn to rec- in the study group vs. 54 percent of needs to be injected subcutaneously ognize these antigens—and coating or sham patients had a recurrence of the twice daily, but patients with diabetes opsonization that will mediate phago- uveitis (n: 153; p<0.001). are used to injections,” says Dr. Cun- cytosis of these bad bits in and around Clearside has a Phase III study of ningham, “so they might not see that the sites of infl ammation. C3 is impor- a microneedle injection of 100 µL of as a huge issue. Also, activating Tie2 is tant for all three effector arms, and so triamcinolone acetonide. The study’s good for vessels in general, not just in in this way could be the better target.” enrollment is complete and data the eye, so there may be some systemic • Allergan is working on an implant from it is expected in the fi rst quarter benefi ts from this treatment, as well. designed to release brimonidine over of 2018. “This is the fi rst and only direct time to battle geographic atrophy, and In a somewhat surprising setback, Tie2 activator,” Dr. Cunningham adds. it showed a therapeutic benefi t in a Santen received a complete response “Others, most notably Regeneron and 2016 study. In the study, reported at letter from the FDA in December Genentech, were seeking to increase the 2016 AAO Retina Subspecialty 2017, informing them that the sub- Tie2 by inhibiting its inhibitor, Ang 2. Day, the 132-µg and the 264-µg im- mission of their uveitis treatment siro- This may be meaningful, and the com- plants reduced the rate of geographic limus was not approvable as submit- pany says it should get superior activa- atrophy progression by 19 and 28 per- ted. When combined, the company’s tion because of its direct Tie2 activa- cent, respectively. SAKURA studies of sirolimus remain tion.” Based on the results of a Phase • Allergan is also studying a time- the largest study of noninfectious uve- IIa proof-of-concept study in which release bimatoprost implant, the Ar- itis of the posterior segment to date (n: AKB-9778 improved patients’ under- temis, for glaucoma. The company is 347 and n: 245). Offi cially, the com- lying retinopathy two or more steps on currently enrolling patients in its Phase pany says it’s reviewing the letter, and the ETDRS diabetic retinopathy scale III trial of the delivery system. The tri- is working closely with the agency to in both eyes, the company has begun a al will compare two sizes of implant— chart the “best path forward.”

8 | Review of Ophthalmology | February 2018

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RP0218_Lombart.indd 1 1/24/18 1:50 PM Monthly MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series

Welcome to the third year of Mackool Online CME! With the generous support of several ophthalmic companies, I am honored to have our viewers join me in the operating room To view CME video as I demonstrate the technology and techniques that I have go to: found to be most valuable, and that I hope are helpful to www.MackoolOnlineCME.com many of my colleagues. We continue to edit the videos only to either change camera perspective or to reduce down time – allowing you to observe every step of the procedure. Richard J. Mackool, MD Episode 26: As before, one new surgical video will be released monthly, “Dense Nucleus: The and physicians may earn CME credits or just observe the case. New viewers Value of Patience” are able to obtain additional CME credit by reviewing previous videos that are located in our archives. Surgical Video by: Richard J. Mackool, MD I thank the many surgeons who have told us that they have found our CME program to be interesting and instructive; I appreciate your comments, suggestions and questions. Thanks again for joining us on Mackool Online CME. Video Overview: Patience is a critically important trait for all CME Accredited Surgical Training Videos Now surgeons to develop and Available Online: www.MackoolOnlineCME.com maintain. In this patient, Dr Mackool demonstrates its value during removal of a Richard Mackool, MD, a world renowned anterior segment ophthalmic red/brunescent cataract in a microsurgeon, has assembled a web-based video collection of surgical one-eyed patient. cases that encompass both routine and challenging cases, demonstrating both familiar and potentially unfamiliar surgical techniques using a variety of instrumentation and settings. This educational activity aims to present a series of Dr. Mackool’s surgical videos, carefully selected to address the specifi c learning objectives of this activity, with the goal of making surgical training available as needed online for surgeons motivated to improve or expand their surgical repertoire. Learning Objective: After completion of this educational activity, participants should be able to: • Assist in the development of a patient, rational approach and game plan when dealing with an extremely dense cataract.

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Amedco and Postgraduate Healthcare Education, LLC (PHE). Amedco is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement Amedco designates this live activity for a maximum of .25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Additionally Supported by: Endorsed by: Jointly Provided by: Supported by an unrestricted independent Review of Ophthalmology® medical educational grant from: Glaukos MST Video and Web Production by: & Crestpoint Management JR Snowdon, Inc Alcon Carl Zeiss Meditec Editorial

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February 2018 | reviewofophthalmology.com | 11

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1 Lemp MA et al. Distribution of Aqueous-Defi cient and Evaporative Dry Eye in a Clinic-Based Patient Cohort: * Non-lipid containing eye drop (Systane Ultra) A Retrospective Study. Cornea. 2012; 31:472-478. Lipid layer thickness (LLT) prior to and 15 minutes following a single drop of emollient or non-emollient eye drop in dry eyes with meibomian 2 gland dysfunction. Data are the mean (±SD) LLT based on stroboscopic video color microscope (SVCM) measurements in study eyes Horwath-Winter J. Prevalence of MGD in an clinical dry eye population. ActaOphthal 2011; 89 (s248)-2334. (qualifying eye in subjects with only one qualifying eye, or the eye with the lowest LLT at baseline in subjects with two qualifying eyes). p<0.001 paired t-test for the change from baseline. p<0.001, n=35, following a single drop. ®/TM are trademarks of Bausch & Lomb Incorporated or its affi liates. © 2018 Bausch & Lomb Incorporated. PN08612 SXP.0018.USA.18

RP0218_BL Soothe.indd 1 1/19/18 11:08 AM February 2018 • Volume XXV No. 2 | reviewofophthalmology.com Cover Focus 26 | Can Corneal Inlays Work For Your Practice? NEW SCHOOL Kristine Brennan, Senior Associate Editor Surgeons discuss the pros and cons of these new devices. OLD SCHOOL 32 | What’s Behind That SMILE Edward Manche, MD A look at patient selection, technique and how SMILE compares to LASIK. 36 | Is There Still a Place for Manual LRIs? Michelle Stephenson, Contributing Editor Not only is there a place, but some surgeons say they’re doing them more now than ever before.

February 2018 | reviewofophthalmology.com | 13

013_rp0218_toc.indd 13 1/26/18 3:21 PM Departments

3 | Review News 22 16 | Editor’s Page New Procedures, Old Expectations

19 | Medicare Q & A What’s New in 2018? There are a number of changes to Medicare that practices should be aware of.

22 | Technology Update The Latest Technology for Toric Alignment New ways to increase accuracy continue to appear. Here’s a sampling of what’s available.

40 | Glaucoma Management Supplements & Glaucoma: Advising Patients 47 Questionable “alternative” treatments are popular, so your patients count on you to set them straight.

47 | Refractive/Cataract Rundown Some New Tricks with Gore-Tex Two ways to use the resilient suture material for fixating IOLs in challenging surgical cases.

50 | Retinal Insider Posterior Scleritis: A Diagnostic Challenge A detailed look at the signs and symptoms, and how to follow up diagnosis with the appropriate therapy.

54 | Research Review Surgical Outcomes of GATT in POAG 55 55 | Pediatric Patient Pearls in Pediatric Ocular Oncology A brief review of diagnosis and treatment for these potentially life-threatening disorders.

61 | Product News

62 | Classifieds

63 | Wills Eye Resident Case Series

66 | Ad Index

14 | Review of Ophthalmology | February 2018

013_rp0218_toc.indd 14 1/26/18 3:21 PM JUST GO

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INDICATIONS AND IMPORTANT SAFETY INFORMATION FOR THE CATALYS® PRECISION LASER SYSTEM Rx Only INDICATIONS: The OptiMedica® CATALYS® Precision Laser System is indicated for use in patients undergoing cataract surgery for removal of the crystalline lens. Intended uses in cataract surgery include anterior capsulotomy, phacofragmentation, and the creation of single-plane and multi-plane arc cuts/incisions in the cornea, each of which may be performed either individually or consecutively during the same procedure. CONTRAINDICATIONS: Should not be used in patients with corneal ring and/or inlay implants, severe corneal opacities, corneal abnormalities, significant corneal edema or diminished aqueous clarity that obscures OCT imaging of the anterior lens capsule, patients younger than 22 years of age, descemetocele with impending corneal rupture, and IMPORTANT SAFETY INFORMATION: INVISIBLE LASER RADIATION any contraindications to cataract surgery. Mild petechiae and subconjunctival AVOID EYE OR SKIN EXPOSURE TO DIRECT OR SCATTERED RADIATION hemorrhage can occur due to vacuum pressure of the suction ring. Potential complications and adverse events include any of CLASS 4 LASER PRODUCT Yb Laser: Laser Class 4/IV CAUTION: Max Output:1030nm,10uJ,1.8W, <900fs Pulse those generally associated with cataract surgery. Should be used only by qualified physicians who have SLD Laser: Laser Class 3R Max Output: 820-930nm, <3.48mW, CW extensive knowledge of the use of this device and have been trained and certified by Abbott Medical Optics/OptiMedica. Per IEC 60825-1:2007 ATTENTION: Reference the labeling for a complete listing of Important Indications and Safety Information.

OptiMedica and CATALYS are trademarks owned by or licensed to Abbott Medical Optics Inc., its subsidiaries or affiliates. ©2017 Abbott Medical Optics Inc. | www.CatalysLaser.com | PP2017CT1303

RP0218_JJ Catalys.indd 1 1/17/18 10:44 AM ® Editor’s Page Walter C. Bethke, Editor in Chief REVIEW E DITORIAL STAFF

Editor in Chief Walter C. Bethke (610) 492-1024 [email protected] New Procedures, Senior Editor Christopher Kent (814) 861-5559 Old Expectations [email protected] Almost since the very beginning of Stanford University’s Edward Man- Senior Associate Editor refractive surgery in the United che, MD, the author of this month’s Kristine Brennan States, surgeons have preached the (610) 492-1008 review of small-incision lenticule importance of managing prospective [email protected] extraction on page 32, implore their patients’ expectations. They say that colleagues to avoid this impulse. many gung-ho patients come in Associate Editor “These patients assume that be- expecting to throw away their spec- Liam Jordan cause SMILE is the newest surgery, tacles and contact lenses, and to walk (610) 492-1025 it’s also the best one, an opinion out seeing 20/20 or better in about [email protected] 20 minutes or so. Surgeons say that that’s common when new technol- if such patients don’t have their sky- ogy arrives,” he says. He then raises Chief Medical Editor high expectations brought closer an interesting point: If you spend Mark H. Blecher, MD (if not all the way down) to earth, your time building up SMILE as and they don’t see like a peregrine the latest and greatest, and either Art Director falcon postop, you’re going to have explicitly or by implication devalue Jared Araujo a diffi cult time making them happy. (610) 492-1032 PRK and LASIK in order to attract Looking at the larger picture, [email protected] patients, what happens when the though the economic downturns in patient either isn’t a candidate for the aughts didn’t do LASIK volume Senior Graphic Designer SMILE, or worse, needs his SMILE any favors, it’s possible that the Matt Egger enhanced postop with PRK? “Not fostering of these lofty expectations (610) 492-1029 only will the patient’s procedure of by some LASIK providers—and [email protected] choice have underperformed for the subsequent negative articles on LASIK complications that started to him, but now you’re telling him he’s International coordinator, Japan appear in the consumer press and got to undergo PRK, the very same Mitz Kaminuma on some patients’ blogs—caused an procedure you degraded during his [email protected] overall souring of the public toward preop visits,” Dr. Manche observes. the procedure, and maybe helped Instead, Dr. Manche says it’s bet- Business Offi ces touch off the FDA study into LASIK ter for refractive surgery in general, 11 Campus Boulevard, Suite 100 outcomes. Newtown Square, PA 19073 and the procedures individually, Fast forward to today, and we (610) 492-1000 if new procedures such as SMILE have new refractive procedures be- Fax: (610) 492-1039 are presented as complementary to ing approved in the United States, the established ones, rather than as but with the same old temptation Subscription inquiries: competitors. This message may not to build them up for patients, espe- United States — (877) 529-1746 be what patients expect when an ex- cially because now marketers can Outside U.S. — (845) 267-3065 slap the classic “new and improved” citing new surgery gets approved, E-mail: label on them. This branding might but it’s what they deserve. [email protected] lead patients to believe that this Website: www.reviewofophthalmology.com isn’t your father’s LASIK with those “gross eye fl aps,” but something better. Some surgeons, such as —Walt Bethke, Editor in Chief

16 | Review of Ophthalmology | February 2018

016_rp0218_edit.indd 16 1/26/18 3:23 PM As demonstrated in phase 3 clinical trials evaluating BCVA,* as measured by ETDRS letters, in patients with Wet AMD, Macular Edema following RVO, DME, and by ETDRS-DRSS† in DR in Patients with DME,1 as well as your clinical experience Start with EYLEA for proven efficacy outcomes1

Dosing driving efficacy outcomes across all indications.1 AMD = Age-related Macular Degeneration; DME = Diabetic Macular Edema; DR = Diabetic Retinopathy; RVO = Retinal Vein Occlusion. Learn more at EYLEA.us/dose

INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS EYLEA® (aflibercept) Injection is indicated for the treatment of patients with • Neovascular (Wet) Age-related Macular Degeneration (AMD): The recommended dose is 2 mg administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not • Acute increases in intraocular pressure have been seen within demonstrated in most patients when EYLEA was dosed every 4 weeks 60 minutes of intravitreal injection, including with EYLEA. Sustained compared to every 8 weeks. Some patients may need every 4 week increases in intraocular pressure have also been reported after (monthly) dosing after the first 12 weeks (3 months). repeated intravitreal dosing with VEGF inhibitors. Intraocular pressure • Macular Edema following Retinal Vein Occlusion (RVO): The and the perfusion of the optic nerve head should be monitored and recommended dose is 2 mg administered by intravitreal injection every managed appropriately. 4 weeks (monthly). • There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. • Diabetic Macular Edema (DME) and Diabetic Retinopathy (DR) in Patients ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or with DME: The recommended dose is 2 mg administered by intravitreal vascular death (including deaths of unknown cause). The incidence injection every 4 weeks (monthly) for the first 5 injections, followed by of reported thromboembolic events in wet AMD studies during the 2 mg once every 8 weeks (2 months). Although EYLEA may be dosed as first year was 1.8% (32 out of 1824) in the combined group of patients frequently as 2 mg every 4 weeks (monthly), additional efficacy was not treated with EYLEA. The incidence in the DME studies from baseline to demonstrated in most patients when EYLEA was dosed every 4 weeks week 52 was 3.3% (19 out of 578) in the combined group of patients compared to every 8 weeks. Some patients may need every 4 week treated with EYLEA compared with 2.8% (8 out of 287) in the control (monthly) dosing after the first 20 weeks (5 months). group; from baseline to week 100, the incidence was 6.4% (37 out of CONTRAINDICATIONS 578) in the combined group of patients treated with EYLEA compared • EYLEA® (aflibercept) Injection is contraindicated in patients with ocular with 4.2% (12 out of 287) in the control group. There were no reported or periocular infections, active intraocular inflammation, or known thromboembolic events in the patients treated with EYLEA in the first hypersensitivity to aflibercept or to any of the excipients in EYLEA. six months of the RVO studies. WARNINGS AND PRECAUTIONS ADVERSE REACTIONS • Intravitreal injections, including those with EYLEA, have been associated • Serious adverse reactions related to the injection procedure have with endophthalmitis and retinal detachments. Proper aseptic occurred in <0.1% of intravitreal injections with EYLEA including injection technique must always be used when administering EYLEA. endophthalmitis and retinal detachment. Patients should be instructed to report any symptoms suggestive of • The most common adverse reactions (≥5%) reported in patients endophthalmitis or retinal detachment without delay and should be receiving EYLEA were conjunctival hemorrhage, eye pain, managed appropriately. Intraocular inflammation has been reported with cataract, vitreous floaters, intraocular pressure increased, and the use of EYLEA. vitreous detachment. Please see adjacent Brief Summary. *Best-corrected visual acuity. †Early Treatment Diabetic Retinopathy Study–Diabetic Retinopathy Severity Scale: an established grading scale for measuring the severity of DR.

Reference: 1. EYLEA® (aflibercept) Injection full U.S. Prescribing Information. Regeneron Pharmaceuticals, Inc. May 2017. EYLEA is a registered trademark of Regeneron Pharmaceuticals, Inc.

© 2017, Regeneron Pharmaceuticals, Inc. All rights reserved. 10/2017 777 Old Saw Mill River Road, Tarrytown, NY 10591 US-LEA-13945

RP0218_Regeneron.indd 1 1/16/18 1:40 PM Less common adverse reactions reported in <1% of the patients treated with EYLEA in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis. BRIEF SUMMARY—Please see the EYLEA package insert Diabetic Macular Edema (DME). The data described below reflect exposure to EYLEA in 578 patients with DME treated with for full Prescribing Information. the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100. Table 3: Most Common Adverse Reactions (*1%) in DME Studies 1 INDICATIONS AND USAGE Baseline to Week 52 Baseline to Week 100 EYLEA is a vascular endothelial growth factor (VEGF) inhibitor indicated for the treatment of: Adverse Reactions EYLEA Control EYLEA Control Neovascular (Wet) Age-Related Macular Degeneration (AMD); Macular Edema Following Retinal Vein Occlusion (RVO); (N=578) (N=287) (N=578) (N=287) Diabetic Macular Edema (DME); Diabetic Retinopathy (DR) in Patients with DME Conjunctival hemorrhage 28% 17% 31% 21% 4 CONTRAINDICATIONS Eye pain 9% 6% 11% 9% 4.1 Ocular or Periocular Infections Cataract 8% 9% 19% 17% EYLEA is contraindicated in patients with ocular or periocular infections. Vitreous floaters 6% 3% 8% 6% 4.2 Active Intraocular Inflammation Corneal epithelium defect 5% 3% 7% 5% EYLEA is contraindicated in patients with active intraocular inflammation. Intraocular pressure increased 5% 3% 9% 5% 4.3 Hypersensitivity EYLEA is contraindicated in patients with known hypersensitivity to aflibercept or any of the excipients in EYLEA. Ocular hyperemia 5% 6% 5% 6% Hypersensitivity reactions may manifest as rash, pruritus, urticaria, severe anaphylactic/anaphylactoid reactions, or severe Vitreous detachment 3% 3% 8% 6% intraocular inflammation. Foreign body sensation in eyes 3% 3% 3% 3% 5 WARNINGS AND PRECAUTIONS Lacrimation increased 3% 2% 4% 2% 5.1 Endophthalmitis and Retinal Detachments. Intravitreal injections, including those with EYLEA, have been associated Vision blurred 2% 2% 3% 4% with endophthalmitis and retinal detachments [see Adverse Reactions (6.1)]. Proper aseptic injection technique must always Intraocular inflammation 2% <1% 3% 1% be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or Injection site pain 2% <1% 2% <1% retinal detachment without delay and should be managed appropriately [see Dosage and Administration (2.7) and Patient Counseling Information (17)]. Eyelid edema <1% 1% 2% 1% 5.2 Increase in Intraocular Pressure. Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal Less common adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal injection, including with EYLEA [see Adverse Reactions (6.1)]. Sustained increases in intraocular pressure have also been detachment, retinal tear, corneal edema, and injection site hemorrhage. reported after repeated intravitreal dosing with vascular endothelial growth factor (VEGF) inhibitors. Intraocular pressure 6.2 Immunogenicity. As with all therapeutic proteins, there is a potential for an immune response in patients treated with and the perfusion of the optic nerve head should be monitored and managed appropriately [see Dosage and Administration EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The immunogenicity data reflect the percentage of (2.7)]. patients whose test results were considered positive for antibodies to EYLEA in immunoassays. The detection of an immune 5.3 Thromboembolic Events. There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the to EYLEA with the incidence of antibodies to other products may be misleading. first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 1% to 3% across treatment groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA were detected in a 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined similar percentage range of patients. There were no differences in efficacy or safety between patients with or without group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported immunoreactivity. thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies. 8 USE IN SPECIFIC POPULATIONS 6 ADVERSE REACTIONS 8.1 Pregnancy The following potentially serious adverse reactions are described elsewhere in the labeling: Risk Summary • Hypersensitivity [see Contraindications (4.3)] Adequate and well-controlled studies with EYLEA have not been conducted in pregnant women. Aflibercept produced • Endophthalmitis and retinal detachments [see Warnings and Precautions (5.1)] adverse embryofetal effects in rabbits, including external, visceral, and skeletal malformations. A fetal No Observed Adverse • Increase in intraocular pressure [see Warnings and Precautions (5.2)] Effect Level (NOAEL) was not identified. At the lowest dose shown to produce adverse embryofetal effects, systemic • Thromboembolic events [see Warnings and Precautions (5.3)] exposures (based on AUC for free aflibercept) were approximately 6 times higher than AUC values observed in humans after 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates a single intravitreal treatment at the recommended clinical dose [see Animal Data]. observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another Animal reproduction studies are not always predictive of human response, and it is not known whether EYLEA can cause drug and may not reflect the rates observed in practice. fetal harm when administered to a pregnant woman. Based on the anti-VEGF mechanism of action for aflibercept [see A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3 studies. Among those, Clinical Pharmacology (12.1)], treatment with EYLEA may pose a risk to human embryofetal development. EYLEA should be 2110 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure used during pregnancy only if the potential benefit justifies the potential risk to the fetus. have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth common adverse reactions (*5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background vitreous floaters, intraocular pressure increased, and vitreous detachment. risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Neovascular (Wet) Age-Related Macular Degeneration (AMD). The data described below reflect exposure to EYLEA in Data 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double-masked, active-controlled Animal Data clinical studies (VIEW1 and VIEW2) for 12 months. In two embryofetal development studies, aflibercept produced adverse embryofetal effects when administered every three days during organogenesis to pregnant rabbits at intravenous doses *3 mg per kg, or every six days during organogenesis Table 1: Most Common Adverse Reactions (*1%) in Wet AMD Studies at subcutaneous doses *0.1 mg per kg. EYLEA Active Control (ranibizumab) Adverse Reactions Adverse embryofetal effects included increased incidences of postimplantation loss and fetal malformations, including (N=1824) (N=595) anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, Conjunctival hemorrhage 25% 28% encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; Eye pain 9% 9% supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the Cataract 7% 7% fetal NOAEL was not identified. At the lowest dose shown to produce adverse embryofetal effects in rabbits (0.1 mg per kg), Vitreous detachment 6% 6% systemic exposure (AUC) of free aflibercept was approximately 6 times higher than systemic exposure (AUC) observed in Vitreous floaters 6% 7% humans after a single intravitreal dose of 2 mg. 8.2 Lactation Intraocular pressure increased 5% 7% Risk Summary Ocular hyperemia 4% 8% There is no information regarding the presence of aflibercept in human milk, the effects of the drug on the breastfed infant, Corneal epithelium defect 4% 5% or the effects of the drug on milk production/excretion. Because many drugs are excreted in human milk, and because Detachment of the retinal pigment epithelium 3% 3% the potential for absorption and harm to infant growth and development exists, EYLEA is not recommended during breastfeeding. Injection site pain 3% 3% The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Foreign body sensation in eyes 3% 4% EYLEA and any potential adverse effects on the breastfed child from EYLEA. Lacrimation increased 3% 1% 8.3 Females and Males of Reproductive Potential Vision blurred 2% 2% Contraception Intraocular inflammation 2% 3% Females of reproductive potential are advised to use effective contraception prior to the initial dose, during treatment, and for at least 3 months after the last intravitreal injection of EYLEA. Retinal pigment epithelium tear 2% 1% Infertility Injection site hemorrhage 1% 2% There are no data regarding the effects of EYLEA on human fertility. Aflibercept adversely affected female and male Eyelid edema 1% 2% reproductive systems in cynomolgus monkeys when administered by intravenous injection at a dose approximately 1500 Corneal edema 1% 1% times higher than the systemic level observed humans with an intravitreal dose of 2 mg. A No Observed Adverse Effect Level (NOAEL) was not identified. These findings were reversible within 20 weeks after cessation of treatment [see Nonclinical Less common serious adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal Toxicology (13.1)]. detachment, retinal tear, and endophthalmitis. 8.4 Pediatric Use. The safety and effectiveness of EYLEA in pediatric patients have not been established. Macular Edema Following Retinal Vein Occlusion (RVO). The data described below reflect 6 months exposure to EYLEA 8.5 Geriatric Use. In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA with a monthly 2 mg dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients were *65 years of age and approximately 46% (1250/2701) were *75 years of age. No significant differences in efficacy or following BRVO in one clinical study (VIBRANT). safety were seen with increasing age in these studies. Table 2: Most Common Adverse Reactions (*1%) in RVO Studies 17 PATIENT COUNSELING INFORMATION CRVO BRVO In the days following EYLEA administration, patients are at risk of developing endophthalmitis or retinal detachment. If the EYLEA Control EYLEA Control eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an Adverse Reactions (N=218) (N=142) (N=91) (N=92) ophthalmologist [see Warnings and Precautions (5.1)]. Eye pain 13% 5% 4% 5% Patients may experience temporary visual disturbances after an intravitreal injection with EYLEA and the associated eye Conjunctival hemorrhage 12% 11% 20% 4% examinations [see Adverse Reactions (6)]. Advise patients not to drive or use machinery until visual function has recovered Intraocular pressure increased 8% 6% 2% 0% sufficiently. Corneal epithelium defect 5% 4% 2% 0% Vitreous floaters 5% 1% 1% 0% Ocular hyperemia 5% 3% 2% 2% Foreign body sensation in eyes 3% 5% 3% 0% Vitreous detachment 3% 4% 2% 0% Issue Date: June 2017 Lacrimation increased 3% 4% 3% 0% Manufactured by: Initial U.S. Approval: 2011 Injection site pain 3% 1% 1% 0% Regeneron Pharmaceuticals, Inc. Vision blurred 1% <1% 1% 1% 777 Old Saw Mill River Road Tarrytown, NY 10591 Based on the May 2017 EYLEA® (aflibercept) Intraocular inflammation 1% 1% 0% 0% Injection full Prescribing Information. Cataract <1% 1% 5% 0% EYLEA is a registered trademark of Regeneron Pharmaceuticals, Inc. Eyelid edema <1% 1% 1% 0% © 2017, Regeneron Pharmaceuticals, Inc. All rights reserved.

RRP0218_RegeneronP0218_Regeneron PI.inddPI.indd 1 11/16/18/16/18 1:411:41 PMPM 019_rp0218_mqa.indd 19 20 1 8 Medicare Update? 2018 Medicare What’s New inthe jor changesinpayment.This year, 2017, ophthalmicimaging had ma- and 23hadnegativechanges. In percent), 19hadpositivechanges codes withsignificantchanges(>3 of morethan3percent.Ofthose 42 haveareimbursementchange gists andoptometristsin2018,only A cent change. care showedanoverall+1.35-per- quirements. HOPDservicesineye if theymeetquality-reportingre- crease of1.9percentto$45.575 schedule conversionfactorin- latory surgicalcentersgotafee- 0.28 percentto$35.9996.Ambu- 2018 conversionfactorwentup misvalued-code adjustments,the of theotherbudget-neutralityand cent MACRAincreaseandsome cians, afterthemandated0.5-per- A Q This articlehasnocommercial sponsorship. Q care fare for 2018? should knowabout.Thismonth,wereviewthemostimportant. There areanumberofchangestoMedicarethatpractices REVIEW Paul M. Larson, MBA, MMSc, COMT, COE, CPC, CPMA Medicare Q&A might applytoophthalmolo- Of the622possiblecodesthat lished FeeScheduleforphysi- In termsofthenationalpub- reimbursement? to changes any there Are changes, how did eye did how changes, payment of terms In taneous or facsiocutaneous flap; flap; facsiocutaneous or taneous CPT code15732( most important,perhaps, isthat endoscopy coding).Inthisarea, face andheadflapsnasalsinus A above forsomeofthesecodes. significant decline.Seethetable fundus photographyshoweda for commonimagingservices,only Q 2018? Implant corneal ringsegments(65785) Implant corneal Level 1E/M(99211) Orthoptics (92265) calculation(92136) Biometry/IOL Fundus photography (92250) Allergy testing(95004) B-Scan (76512) Epilation (67820) Visual Evoked Potential—except glauc. (95930) Samples ofCPTCodesWithSignificant ChangesIn2018

the mostchanges(relatedto Oculoplastics istheareawith Category I CPT codes for codes ICPT Category to changes any there Are Muscle, myocu- Muscle, February 2018 head and neck [e.g., temporalis, temporalis, [e.g., neck and head ply now(usually1404xand1406x). with SOOFliftssoothercodesap- leted. Thiswassometimesused masseter muscle, sternocleido- muscle, masseter maticofacial fl ap) with preservation of of preservation with flap) maticofacial mastoid, levator scapulae] levator mastoid, ous or facsiocutaneous flap; head head flap; facsiocutaneous or ous vascular pedicle; vascular and neck with named vascular ped- vascular named with neck and icle (e.g., buccinators, genioglossus, genioglossus, buccinators, (e.g., icle temporalis, masseter, sternoclei- masseter, temporalis, domastoid, levator scapulae); and scapulae); levator domastoid, • Other codeswithchangesare: • 15733—Muscle, myocutane- 15733—Muscle, • 15730—Midface fl ap (i.e., zygo- (i.e., fl ap 15730—Midface | reviewofophthalmology.com +17% +7% +4% -14% -14% -21% -23% -23% -84% ) isde- |

19 1/26/18 3:37 PM Medicare

REVIEW Q&A

• 95930—Visual evoked poten- segment aqueous drainage de- Are there changes to the tial (VEP) checkerboard or flash vice, with creation of intraocular Q Quality Payment Program testing, central nervous system reservoir, internal approach, into that was new only last year? except glaucoma, checkerboard the supraciliary space. (This is the or flash, with interpretation and code for the CyPass Micro-Stent.) 2018 is the second year of QPP report (Underlined text was added A and there are some changes. to the code and strikethrough was Are there HCPCS code Avoiding a Merit-based Incen- deleted.) Q changes to be aware of? tive Payment reduction remains o With VEP for glauco- straightforward but the threshold ma (all types), code 0464T (Visual For Medicare, the exist- is raised from three points in 2017 evoked potential testing for glau- ing code for Omidria, C9447 A to 15 points in 2018. The maximum coma, with interpretation and re- (phenylephrine and ketorolac, in- port) has applied since January jection) had its pass-through pay- bonus or penalty rises to 5 per- 2017. ment status changed. The payment cent from the current 4 percent. indicator for this code changed The Exceptional Performance Are there any new CPT from “K2” (paid separately) to “N1” threshold stays at 70 points. The Q Category III codes? (bundled). This means that on Jan- exemptions for MIPS are raised to uary 1, 2018, payment for C9447 $90,000 in allowed charges or 200 Category III codes are re- is packaged in the reimbursement Part B patients. A leased twice a year. Coverage for the cataract procedure and is There were also changes to the and payment for these codes are no longer separately identifiable relative weights and thresholds at the discretion of the individual for Part B Medicare. within the four MIPS components. Medicare Administrative Contrac- An Advance Benefi ciary Notice or In 2018, quality contributes 50 tors. None are significant for eye similar fi nancial waiver form cannot percent (down from 60 percent); care on January 1, 2018, but those be used to shift the payment respon- advancing care information, 25 that are in place and effective sibility to the Medicare benefi ciary. percent; clinical practice improve- since July 1, 2017 are: • 0469T—Retinal polarization Are there new things ment activities, 15 percent; and scan, ocular screening with on-site Q to be aware of from resource use (Cost), 10 percent automated results, bilateral; the Office of the Inspector (up from zero). The “threshold of • 0472T—Device evaluation, General? patient” percentage for quality in interrogation and initial program- each of the six measures rises from ming of intraocular retinal elec- The OIG no longer publish- 50 percent to 60 percent. trode array (e.g., retinal prosthe- A es an annual Work Plan as a sis), in person, with iterative ad- separate document. It now does Were there changes to justment of the implantable device monthly updates on its website. Q ICD-10? to test functionality, select opti- Issues such as misuse of modifiers mal permanent programmed val- (e.g., 24, 25, and 59) continue to As with ICD-9, these go into ues with analysis, including visual draw scrutiny. Oversight related to A effect on October 1 each year. training, with review and report the new Quality Payment Program There are a few subtle changes, by a qualified health care profes- continues. but the biggest relate to myopic sional; degeneration (H44.2-) and low • 0473T—Device evaluation Has Medicare made vision/blindness coding (H54.-), and interrogation of intraocular changes of significance Q each of which gained much greater retinal electrode array (e.g., reti- to beneficiaries? nal prosthesis), in person, includ- specificity. ing reprogramming and visual The 2018 Medicare Part B de- training, when performed, with A ductible remains the same as Mr. Larson is a senior consultant review and report by a qualified it was: $183. The standard monthly at the Corcoran Consulting Group. health care professional; and premium also remains unchanged Contact him at plarson@corcoranccg. • 0474T—Insertion of anterior at $134. com.

20 | Review of Ophthalmology | February 2018

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RP0218_Icare.indd 1 1/26/18 4:11 PM Technology Update

REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD

The Latest Technology For Toric Alignment New ways to increase accuracy continue to appear. Here’s a sampling of what’s available. Christopher Kent, Senior Editor

s the popularity of toric intra- toric IOL to its optimal position. Aocular lenses slowly increases, op- The company notes that the Lensar tions to help align them accurately System’s astigmatism-management have proliferated. The time-honored features include: method of accomplishing this was • integration of all corneal mea- simply to use ink to mark the desired surements, including total corneal axis on the eye preoperatively. That refractive power and total corneal approach has left plenty of room for astigmatism, to guide placement of better alternatives, however, since it arcuate incisions; tends to produce less-than-perfect • iris registration with automatic results. Ink marks can be broad rather cyclorotation adjustment; than precise and can fade or smudge • arcuate incision planning; and by the time the patient is on the op- • surgeon tables for managing pre- The IntelliAxis-L System is a new upgrade erating table. And as most surgeons now available for the Lensar Laser System. existing and surgically-induced astig- know, a small error in rotational align- matism. ment can undercut the effectiveness the laser as the only one on the mar- For more information, visit: lensar. of a toric IOL signifi cantly. ket developed specifi cally for cataract com/features.php Here, you’ll fi nd a sample of some surgery. of the more recent options designed IntelliAxis-L uses Lensar’s diagnos- Tocular System to help surgeons achieve accurate tic capabilities, iris registration soft- toric alignment. ware and intraoperative imaging to The Tocular System (Haag-Streit precisely and “permanently” identify Surgical) is a rotatable, wide-angle IntelliAxis-L System the location of the steep corneal axis ocular with a clearly visible integrated at the capsular plane for toric IOL reticle in the center of the visual fi eld. One of the newest entries in this alignment. The system creates cus- The device can be rotated manual- area is the IntelliAxis-L system, now tom marks, which the company says ly via a sterilizable knob, and it can part of the latest upgrade to the Len- can’t be duplicated by any other de- achieve IOL alignment within two sar Laser System (Lensar), which was vice currently available, which remain degrees of the target axis. The eye showcased at the American Academy visible postoperatively to help iden- must be marked preoperatively us- of Ophthalmology meeting in No- tify any unexpected rotation and help ing a marking system of your choice. vember 2017. The company describes guide any needed realignment of the (Haag-Streit recommends the Davis

22 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

022_rp0218_tech.indd 22 1/26/18 4:20 PM premarking system, available from is the fi rst self-leveling corneal marker part of Haag-Streit’s T-Cone Toric John Weiss.) After the IOL is implant- with pre-inked, sterile, disposable tips Platform, an optional addition to the ed, the surgeon adjusts the micro- and an integrated fi xation light. The LenStar biometer. The T-Cone Toric scope zoom to visualize the ink marks, device has a concealed dual-pendu- Platform complements the LenStar’s and then rotates the Tocular reticle to lar weight system balanced between comprehensive measurement spec- align with them. The IOL can then be two high-precision ball-bearings that trum with 11-ring placido topography, aligned using the medium and small ensures that the RoboMarker ring to help confi rm the axis location and reticle markings as a guide. dial will maintain your chosen axis to the regularity and symmetry of the For more information visit: haag- within one degree. astigmatism. Toric IOL calculation streit.com/fileadmin/Haag-Streit_ is accomplished with the integrated Surgical/Download_documents/Bro- Barrett Toric Calculator. chures/Flyer_TOCULAR.pdf Planning the operation using high- resolution eye images allows the user Verion Image Guided System to defi ne additional guiding lines to anatomical landmarks that will be rec- The RoboMarker System from Surgilum. The Verion’s Reference Unit (Alcon) ognizable in the intraoperative view. is a modifi ed keratometer that takes The planning sketch can be printed corneal power measurements, cap- For marking the cornea, the system and hung near the microscope. tures a high-resolution reference provides single-use, sterile “Robo- For more information, visit: haag- image, automatically detects scleral Tips”— “fi ns” that come pre-applied streit.com/haag-streit-diagnostics/ vessels, as well as the limbus, the pu- with a dry marking formula. When products/biometry/t-cone-toric-plat- pil and iris features, and then shows the dry formula contacts the tear fi lm, form/ where the steep axis is relative to a it produces precise marks that last up picture of the eye. The data captured to two hours, long enough for preop- Cataract Suite Markerless by the Reference Unit is then dis- erative marks to still be clear in the played in the Verion Digital Marker, operating room. The system includes The Cataract Suite Markerless from which is compatible with the LenSx a fi xation light to help replicate the Carl Zeiss Meditec is a set of intercon- laser and most surgical microscopes. position of the patient’s eye when you nected instruments that enables— measured the astigmatism preopera- among other things—toric IOL and tively. The RoboTips are available in limbal relaxing incision alignment either visible-spectrum or infrared without the need to mark the eye. formulas (the latter being useful un- Data transfer between instruments der the infrared lighting sometimes is managed by Zeiss’s FORUM data- used by the Catalys and Lensar instru- management system, eliminating the ments, as well as intraoperative aber- need for manual transfer of informa- rometry systems). tion and greatly increasing surgical The Verion Image Guided System is The company claims that this mark- effi ciency, according to the company. compatible with most surgical microscopes. ing system can save time compared After the IOLMaster takes its mea- to some multistep marking protocols. surements and captures an image of The Digital Marker software tracks For more information visit: surgilum. the eye, providing a digital overlay com/products/robomarker/ to help with alignment. It can also provide guides for relaxing incisions, EyeSuite Toric Planner creating the capsulorhexis and posi- tioning a multifocal lens. For more The EyeSuite Toric Planner (Haag- information, visit: myalcon.com/prod- Streit) enables the surgeon to intui- ucts/surgical/verion-guided-system/ tively plan the surgery using high- resolution images of the eye. It also RoboMarker System features an incision-optimization tool to help the surgeon minimize resid- According to the manufacturer ual astigmatism by placing the inci- Zeiss’ Cataract Suite Markerless works with (Surgilum), the RoboMarker System sion in the right spot. The Planner is the IOLMaster and Callisto eye system.

February 2018 | reviewofophthalmology.com | 23

022_rp0218_tech.indd 23 1/26/18 4:20 PM Technology

REVIEW Update

the eye, the information, including tems) employs iris fi ngerprinting to corneal astigmatism data, is trans- improve the accuracy of toric implant ferred to the Callisto eye system. Cal- alignment. A detailed, high-resolution listo eye superimposes templates of photograph of the dilated pupil is planned surgical incisions, limbal re- captured during the initial preop ex- laxing incisions, the capsulorhexis and amination. The keratometric merid- the toric lens target axis over the eye ians and the IOL goal line, transposed in the eyepiece and heads-up display from the toric IOL calculator, can be of a Zeiss microscope. It matches the overlaid on the image in the form of reference image to the patient’s eye, a protractor. That image can then be tracking in real time using unique al- brought into the OR on a USB drive gorithms from Zeiss. With Callisto or printed as a hard-copy photograph eye markerless alignment, Zeiss says When using the Illuminating Surgical for reference during the IOL align- that manual marking steps can be Keratoscope V5, the two refl ections reveal ment. The surgeon locates at least the toricity of the lens and cornea, helping skipped altogether for a more precise two unique landmarks in the iris such the surgeon to align the lens. toric IOL alignment. as crypts, nevi or brushfi elds. During This function is integrated into of alignment and patient outcomes. surgery, those landmarks act as guides Zeiss’s OPMI Lumera 700 micro- For more information, visit: mastel. to help the surgeon use a Mendez scope; for all other current Zeiss sur- com/product/mastel-isk/ guiding ring to accurately match the gical microscopes, it’s available as a target meridian shown in the image. retrofi t. For more information, visit: Discovery System For more information, visit: eye- zeiss.com/meditec/us/products/oph- photosystems.com/toric-alignment/ thalmology-optometry/cataract/zeiss- The Discovery System (Innovative cataract-suite-markerless.html Visual Systems) measures multiple Wet-Field Osher ThermoDot eye characteristics including white-to- Marker Illuminating Surgical white, pupil diameter, corneal topog- Keratoscope V5 raphy and both corneal and whole-eye The Osher ThermoDot Marker higher-order aberrations, using wave- (Beaver-Visitec International) is a bi- The fifth-generation Illuminating front technology. The system provides polar intraoperative instrument that Surgical Keratoscope (Mastel) fea- toric IOL axis orientation (to ANSI makes a tiny pinpoint cautery mark on tures visual axis fixation/centration precision standards), while iris reg- the cornea, eliminating the need for and lights indicating the primary istration corrects for head tilt and/or ink. The fi ne dot(s) can be used as a meridian, adjustable from 0 to 180 cyclorotation. Together, retroillumi- precise reference point for a variety of degrees. The device is designed to ac- nation photography and iris registra- procedures, including astigmatic ker- count for cyclotorsion. The surgeon tion enable precise, direct assessment atotomy and toric intraocular lens im- marks the eye at 3, 6 and 9 o’clock of IOL orientation. The Discovery with the patient upright. Intraopera- System also provides postoperative tively, while the patient fi xates on a astigmatism analysis and repositioning pulsating red light, the surgeon aligns guidance, showing how to correct any the LED cardinal references with the error in toric IOL alignment. In addi- pre-marks and sets the primary me- tion, once the surgeon has entered the ridian to the desired position. The de- patient’s corrected axis, the Discovery vice can be attached to most surgical System will display a simulated image microscopes, with standard sizes for equivalent to a 20/30 letter on the Zeiss and Leica scopes. Snellen chart, showing the expected The manufacturer notes that this visual acuity after IOL repositioning. device is not intended as a sole indi- For more information, visit: ivisual- cator of absolute alignment, but as a systems.com/index.html complement to a systematic approach to accurate IOL alignment. With ex- Osher Toric Alignment System The Osher ThermoDot device creates a tiny, perience, the company says, the sys- painless cautery mark that will not smear, tem will greatly improve the accuracy This system (from Eye Photo Sys- but disappears after a day or two.

24 | Review of Ophthalmology | February 2018

022_rp0218_tech.indd 24 1/26/18 4:20 PM COMBO CHAIRS & STANDS plantation. Because no ink is involved, analyzes postop data to aid in variable the precise, easily visible mark will not optimization. According to Alcon, the smear and will last the duration of the ORA System can reduce the num- surgery. (The mark is so small that it ber of patients falling outside of the isn’t even felt by the patient; it disap- intended astigmatic target by almost pears in a day or two.) The unique 54 percent compared to conventional curved design of the marker facilitates preoperative calculations. For more OptimizeOptimize a perpendicular approach. information, visit: myalcon.com/prod- For more information visit: beaver- ucts/surgical/ora-system/ spacespace anandd visitec.com/upload/BVI_SellSheet_ WetField_Osher_ThermoDot_ TrueGuide functionality.functionality. LowRes.pdf TrueGuide (TrueVision 3D Sur- Optiwave Refractive Analysis gical) is a software application that System, with VerifEye+ generates templates in the surgeon’s surgical fi eld of view, in real time, to The ORA intraoperative system aid in IOL alignment and incision cre- (Alcon) measures the eye’s refractive ation, employing customized surgeon state while the patient is on the table, profi les. It uses autoregistration with providing continuous assessment and a preoperative image and 3-D eye- recommendations for lens power— tracking that helps to eliminate paral- including the axis and magnitude of lax errors during the alignment. astigmatism. Because this approach measures the total refractive state of the eye, including posterior corneal astigmatism, it helps to improve astig- matic outcomes, the company states.

The TrueGuide system generates templates in the surgical fi eld of view in real time.

TrueGuide provides real-time vec- tor analysis for incision optimization and toric IOL and LRI positioning, taking all variables into account; it updates its calculation of predicted Affordable,Affordable, residual astigmatism as the surgeon proceeds. Touchscreen capability at space-savingspace-saving The ORA intraoperative system shows the microscope enables surgeons to real-time streaming data, taking posterior cchairhair & standstand corneal astigmatism into account. change toric IOL alignment, incision parameters and targeted astigmatic The system provides overlays show- outcomes at any time. After surgery, it solutions. ing the optimum positioning for lim- employs regression analysis of postop Small footprint bal relaxing incisions, and then pro- diagnostics to improve the surgeon’s 41.2” x 34.2” vides continuous validation of LRI nomogram. The company says the placement and the anticipated impact system is compatible with any surgi- on visual outcomes. The real-time cal microscope; it allows cloud-based streaming data allows surgeons to ro- input of patient data from any location tate a toric lens within one degree of and also acts as an archiving system. the desired axis. In addition, the sys- Visit truevisionsys.com/trueguide. tem’s AnalyzOR feature collects and html for more information.

022_rp0218_tech.indd 25 1/26/18 4:20 PM Refractive Surgery REVIEW Cover Focus Can Corneal Inlays Work for Your Practice?

Kristine Brennan, Senior Associate Editor

Surgeons discuss orneal inlays are intended vard Eye Associates in Laguna Hills, to be simple, lifelong inter- believes that incorporating corneal the pros and Cventions to end or reduce inlays into refractive practice is well spectacle dependence—and its ac- worth the effort, but notes that they cons of this companying inconvenience—for haven’t penetrated the market deep- presbyopes, who, according to one ly. “I think we surgeons as a popula- new approach 2008 study, are projected to num- tion have been pretty hesitant to take ber approximately 1.37 billion glob- up inlays. There is a learning curve to refractive ally by 2020.1 Speaking to surgeons for us, and a phase of patient educa- who are in the know, however, you tion that we need to go through,” correction. learn that their colleagues have been he says. He says ReVision Optics’ slow to adopt this new technology, as closing and discontinuation of the demonstrated by the recent shutter- Raindrop was a result of several ing of ReVision Optics, maker of the factors. “The technology itself was now-discontinued Raindrop inlay. a good performer,” he says. “It was Potential roadblocks to success with good enough for me to implant two inlays include variations in individual inlays in close, personal friends, both wound healing postoperatively and of whom were quite happy. Person- tear-fi lm diffi culties, as well as po- ally, I believe the slow adoption of tential unwanted side effects from the Raindrop inlay was attributable to postop topical steroids.2 the ‘competition’ of great results with Here, surgeons who offer corneal LASIK and premium IOLs. While inlays—both the Kamra and the de- neither procedure is ideally suited to funct Raindrop—weigh in on who’s the emmetropic presbyope who was getting them, the mechanics of im- a candidate for Raindrop, both have planting them, their pros and cons, received wide public acceptance and and where they think the future of adoption by surgeons. In addition, inlays is headed. achieving a quiet eye with the Rain- drop inlay required more follow-up Slow Adoption and diligence after surgery than other refractive procedures.” John A. Hovanesian, MD, clini- Currently, ophthalmology has cal instructor at the Jules Stein Eye been slow to dive into inlays. It’s pos- Institute, University of California, sible that, as Dr. Hovanesian notes, Los Angeles, and in practice at Har- surgeons aren’t interested in cresting

26 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

0026_rp0218_f1_revised.indd26_rp0218_f1_revised.indd 2266 22/2/18/2/18 12:5312:53 PMPM a new learning curve. In terms of Eye Centers in Toronto and San safety and effi cacy, in the absence of Francisco, became part of the inlay a lot of large-scale, postmarket data, market in August 2012, when he de- U.S. ophthalmologists have the FDA cided to get a Kamra implanted in trials to go on for the Kamra (Acu- his own eye. “There’s sort of a mo- Focus; Irvine, California) and the ment that hits you where all of a sud- discontinued Raindrop. The FDA’s den, you feel your age,” he says. “For summary report on the Kamra shows me, it was the size of the font on my that of the 508 operated eyes studied, iPhone—and my teenage daughter 44 (8.7 percent) had had the inlay who tormented me about it for an en- removed at 36 months, with unac- tire day. I said to myself, ‘Okay, that’s ceptable hyperopic shift (25/44) cited it. I need to do something.’ ” as the most frequent cause. (For the A refractive surgeon with 27 years subgroup of 166 eyes implanted per of experience at the time, Dr. Machat the instructions currently in force, sought a treatment with a high safety seven had the Kamra removed.)3 profi le. “A corneal inlay made a lot For the Raindrop, 27 of 373 oper- of sense to me,” he recalls. At the ated eyes (7.2 percent) studied in ASCRS meeting that year, he listened the FDA trial had that inlay removed to John A. Vukich, MD, present early at 36 months. Haze and patient dis- FDA data on the Kamra. Dr. Vukich satisfaction with visual outcome after closed with a case presentation, in three months postop were tied as the which he revealed that he was in fact top reasons for explantation at 10 the subject. Dr. Machat recalls that cases out of 27 apiece.4 he was convinced to proceed after “We know they can work, because questioning Dr. Vukich post presen- there are practices that are really suc- tation. “I went ahead and had it done ceeding with them,” Dr. Hovanesian myself with Dr. Minoru Tomita in says. “We refractive surgeons need to Japan, and I was really thrilled. I had try and make this a successful addi- a very fast visual recovery. The very tion to our surgical armamentarium.” next day I was already J1, and three days later I was operating,” he says. Who’s Getting Them? Shortly after the procedure, Dr. Machat integrated the Kamra into his Surgeons say that, in the right pa- Toronto practice. “We got approval tients, the inlays can work well. [from Health Canada] in September Dr. Hovanesian says that inlays are 2012. At that time, they were still aimed at emmetropic presbyopes, doing thick corneal fl aps, not pock- who are a tricky group to satisfy. ets, for insertion of the inlay. But we “These patients have low refractive rapidly learned that a pocket deeper error but desire freedom from eye- in the cornea was a better approach glasses for reading. Such patients surgically and we got far better re- tend to be in their late 40s to 50s,” he sults, so there was defi nitely a learn- says. “They don’t have signifi cant cat- ing curve,” he says. aract yet and they’re highly motivat- The current version of the Kamra ed to do something. They have heard inlay is a dark polyvinylidene fl uoride of LASIK; most of them have heard ring etched with perforations, 6 µm of monovision, but many have a bias thick and 3.8 mm in diameter. Its against it. A traditional approach is central aperture is 1.6 mm, and it unlikely to apply very well to them, is placed over the fi rst Purkinje im- making inlays a good fi t.” age when implanted into a stromal Jeffery J. Machat, MD, FRCSC, pocket 200 to 250 µm deep. Long- DABO, medical director of Nvision term data suggest that the Kamra

026_rp0218_f1_revised.indd 27 2/2/18 12:53 PM Cover Refractive Surgery

REVIEW Focus

Of the 44 explanted Kamras in the FDA pivotal study cohort, two were removed for cosmesis.3 When he combines inlays with LASIK, Dr. Hovanesian notes it’s im- portant to adjust the refractive tar- get. “In those who are more myopic it’s best to undercorrect the nondom- Jeffery J. Machat, MD, FRCSC, DABO FRCSC, MD, Machat, Jeffery J. inant eye with the intention of later putting in a Kamra,” he explains. Dr. Hovanesian looks forward to the FDA approval of the Flexivue Because it is made of dark polyvinylidene fl uoride, the Kamra small-aperture inlay may be Microlens (Presbia Coöperatief U.A.; visible in eyes with light-colored irises. Irvine, California), a refractive in- lay 3 mm in diameter made of clear results in notably improved monocu- or they are hyperopic. They under- UV-blocking copolymer. The central lar and binocular uncorrected near stand that they have to wear reading zone has zero refractive power and and intermediate vision, with a small glasses over their contact lenses if a 0.15-mm hole. Its peripheral zone loss of monocular and binocular un- they’re hyperopic; or if they’re myo- comes with add powers ranging from corrected distance visual acuity. In a pic above -4 D, they can’t take their +1.25 to +3.5 D in 0.25-D incre- study with fi ve-year follow-up, mean glasses off and read comfortably. ments. The Microlens varies in thick- UNVA at 60 months was improved These individuals all understand the ness from 15 to 20 µm, depending on from J7/J8 preoperatively to J3 ±2 inconvenience of presbyopia, and add power. “It’s still undergoing FDA lines. Of 32 patients, two required re- they also understand that being able trials. But so far, the data look good centration of the inlay at six months; to have that extended depth of focus and it should offer promise as anoth- one Kamra was explanted due to un- and freedom from reading glasses— er valuable entrant into this market,” satisfactory hyperopic shift; one pa- or a least a signifi cantly diminished he says. The multicenter Phase III tient had epithelial ingrowth in the need for them—is a real benefit,” trial will follow approximately 412 early postop period.5 Notably, the says Dr. Vukich, who offers the patients between 45 and 60 years old study patients got their inlays from Kamra inlay to his patients. implanted with the Microlens. The 2006 to 2007, and so were implanted study is expected to wrap up in early with an earlier version of the Kamra Making It Work 2019 (ClinicalTrials.gov Identifier: that was 10 µm thick, etched with NCT02110472). fewer holes and that allowed more Dr. Hovanesian notes that a pa- In a study of 47 emmetropic pres- unfocused light onto the retina. tient’s preop refraction is important byopes with the Microlens inserted John A. Vukich, MD, associate when placing an inlay. “I tend to in a femtosecond laser-created cor- clinical professor of ophthalmology prefer the Kamra for patients who neal pocket 280 µm deep, no compli- at the University of Wisconsin Madi- are slightly myopic,” he says. “As we cations occurred over the 12-month son School of Medicine and in pri- know, the ideal patient for the Ka- follow-up period, and 75 percent of vate practice at Davis Duehr Dean mra is about -0.75 D. For the Rain- the patients achieved uncorrected Eye Care in Madison—and the im- drop, the ideal patient was more like near visual acuity of 20/32 or better petus for Dr. Machat’s decision to get a +0.75 D. in the operated eye. The operated his own inlay—says that most of his “Another thing to consider is that eyes’ mean uncorrected distance inlay patients present as prospective there is a little cosmetic concern with acuity dropped from 20/20 preop to LASIK patients. “The most common the Kamra, particularly for people 20/50 (p<0.001), while mean bin- inlay patients that we treat are indi- with lighter-colored eyes, because it ocular UDVA did not change signifi - viduals who are interested in LASIK can be visible to the patient,” contin- cantly (p=0.516).6 to begin with, and then this creates ues Dr. Hovanesian. “I’ve not actu- “I’ve done the Microlens in Canada,” a value-added option,” he explains. ally had anyone who’s received it and says Dr. Machat. He observes that pa- “Patients who are looking for LASIK been unhappy with it, regardless of tients could start with one Flexivue in the presbyopic range are generally eye color, but I think it’s a conver- lens power and then replace it with a either higher myopes (-4, -5, -6 D) sation worth having with patients.” higher one as presbyopia progresses,

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026_rp0218_f1_revised.indd 28 2/2/18 12:53 PM but also that patients getting inlays Majid Moshirfar, MD curs Dr. Vukich, who also says that generally won’t do this. “We have the majority of his Kamra patients found in our very limited experi- need to be brought to plano or -0.5 ence that patients do not want to put to -0.75 D of sphere correction in in an inlay and then come back in their nondominant eye to prepare two or three years for another one. for the inlay. From a patient’s-reality perspective, The Kamra obstructs the view of a most people will just put in a +2.25 small portion of the retina. The FDA D Microlens and that’s it. Patients summary report on the Kamra warns were losing more distance than we that medical laser treatments for expected, but getting good reading,” certain eye conditions may warrant he says. extra caution or even removal of the A surgeon opens the pocket in preparation inlay.3 “Retinal surgeons initially felt Lifelong Implant for sliding in the Kamra presbyopic like there might be some obstructed intracorneal inlay. view, but that hasn’t turned out to be “I’m excited about corneal inlays the case,” says Dr. Vukich. “You can because I think of them as a life- sure that I have achieved my target see around them quite easily.” long procedure for patients. With the refraction. Let’s say they’re +3 D and Dr. Hovanesian doesn’t think they Kamra, we’re altering the cornea to I’m targeting -1 D, which would be pose much of a visibility problem in allow depth of focus, and that change about the maximum I would do on the event of future retinal evaluation in shape lasts the rest of the patient’s a cornea that’s fl at and not dry. Or and treatment, either. “Some retinal life, even after a cataract surgery,” let’s say they’re -8 D. I want to wait specialists are concerned about this says Dr. Hovanesian. “We have in and make sure that they don’t re- with the Kamra, but if you have a pu- fact done cataract surgery on patients gress. In those cases, I’ll do LASIK, pil that dilates reasonably well then who have previously undergone wait a month, refract them to make it’s really not an issue to see around Kamra as part of the FDA study pri- sure I’ve hit my target refraction, and it,” he says. “It’s like looking around a or to approval, and those patients then I’ll go ahead and insert the inlay. tiny corneal scar: You still see around have done very well.” But if there’s no clinical reason not it if the cornea is clear outside the Dr. Machat concurs that corne- to, then I do it all the same day. area of the inlay.” al inlays can last a lifetime without “I’ll do LASIK for about 80 per- complicating future ophthalmic in- cent of my corneal inlays,” Dr. Ma- Challenges with Inlays terventions. “The Kamra inlay and chat continues. “So this has increased the Raindrop inlay continue to work my LASIK practice. We often have Some surgeons think the slow until someone develops a cataract,” patients who are early presbyopes adoption rate of corneal inlays among he says. “I’m going to leave my cor- and we just leave them a little bit surgeons may just be explained by neal inlay in once I develop lenticular undercorrected; that’ll put off their their relative novelty on the refrac- opacities, and just put in a monofocal need for readers for about fi ve years, tive scene. IOL and target -1 D for reading. I and then they’ll come back as soon “The challenge with inlays is a lack won’t need to put a multifocal in my as they need a corneal inlay. All of a of familiarity on the part of the gen- left eye; I won’t need to remove it. I sudden, that inlay takes the -0.75 D eral public,” says Dr. Hovanesian. won’t need to do anything,” he says. and gives them 3 D of accommoda- “When we started doing LASIK years Dr. Machat will do LASIK and in- tive range, so they’re thrilled. We’ve ago, it was perceived as a cutting- lays on the same day or break up the done them in pseudophakes; we’ve edge, possibly risky new procedure. procedure, depending on the clinical done them in post-LASIK patients People had questions about safety; indications. “LASIK takes about six and post-PRK patients, as well as in they had questions about long-term minutes; a Kamra inlay, once you get virgin corneas. It’s defi nitely worked stability of results. Today, 20 years experienced, takes about six min- well for us.” later, everyone has friends who’ve utes,” he says. “But if someone has a “In terms of this being a treatment been through LASIK and who’ve had high prescription or a complex pre- for life, our experience has been that positive things to say about it. Inlays scription, or a lot of preoperative dry- you can certainly do a cataract sur- are like LASIK was 20 years ago. eye concerns, then I’ll break up the gery with these inlays in place, and We have to help patients understand procedure because I want to make it really doesn’t get in the way,” con- what they are, how they work, and

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REVIEW Focus John A. Hovanesian, MD what their benefi ts are.” need to train your staff to do a little “It’s not unlike the early days of more handholding for postoperative LASIK surgery,” agrees Dr. Vukich. inlay patients than for post-LASIK “It took a couple of years before pa- patients. “There’s a little bit of heal- tients really understood and knew ing time. There’s a little bit more someone who’d had it done,” he says. follow-up care,” he notes. He adds “It’s true that we’re not seeing huge that some inlay patients may need numbers at this point, but it is quietly a reminder of their preop vision to and steadily gaining momentum.” appreciate how far they’ve come Dr. Machat introduces a corneal postoperatively. “Some patients get inlay as an improvement on LASIK an inlay, and six months later they alone. “We present it to patients as an The Raindrop was a nonrefractive inlay kind of forget what their preop vi- upgrade, he says. “If you get LASIK, made of clear hydrogel. It approximated the sion was like. One thing that we ac- you’re going to get distance vision cornea’s refractive index. tually learned to do from the FDA but you’re going to need reading study—and I recommend this to all glasses. Patients ask if there are any understand presbyopia. I gave a pa- surgeons—is to take a little hand- other options. We like the corneal in- tient consultant on my staff LASIK held 8.5 x 11-inch reading card, and lay because patients retain binocular because she was a moderately high have the patient read the smallest distance vision. If someone has -1 D myope, and I inserted a Kamra inlay. print they can on it. Have them sign monovision, that monovision will only She was then able to really talk to our it, and put it in their chart. Later, last so long, whereas with an inlay it patients about it.” if they’re wondering if their inlay is will last for decades. It’s resistant to In addition to educating patients doing anything for them, you can the progression of presbyopia. about the benefi ts of corneal inlays, pull that card out and show them. “The word of mouth has been quite setting their expectations is also key. They can always read much better dramatic,” Dr. Machat continues. “If “You have to tell patients ahead of after the procedure than before and you think of myopes, one in four of time that vision does improve, but sometimes they’re amazed at what a their friends are myopic: When you it may take a couple of weeks, and difference it’s made. They simply for- think of presbyopes, 100 percent of sometimes, it may take even a little got how bad their previous reading their friends are presbyopic. Having longer before they get the full ef- vision was. Sometimes you just have presbyopic solutions that go beyond fect,” stresses Dr. Vukich. “I simply to remind patients of what you’ve multifocal IOLs is a vital part of any tell patients, ‘It’s going to take a little done for them.” refractive practice.” while, so if you’re not getting the full Having experienced the Kamra as Dr. Hovanesian says that his staff effect, we anticipate that. It takes both a patient and a surgeon affords and co-managing optometrists help awhile for things to settle down and Dr. Machat insight when answering get the word out about corneal in- for the ocular surface to optimize patients’ questions about potential lays. “We have folks in the practice and for the healing to take place,’” he near-vision difficulty under meso- who do that very well, along with says. “Patients need to know what to pic conditions. “All presbyopes have some docs outside. Just like there expect.” trouble when it’s dark,” he says, “but was with LASIK, there’s a bit of edu- it’s not like the inlay makes your vi- cation mode that the co-managing Fine-tune Your Follow-up sion much darker, so that you sud- doctors have to engage in,” he says. denly have to use a light when you “Train your staff,” urges Dr. Mach- “There is clearly a period of post- didn’t previously. But there is also at. “Get them on board. Really make operative care that is necessary with retinal adaptation occurring. It’s very sure that they understand, because inlays,” Dr. Vukich continues. “These interesting.” Dr. Machat says he ex- this is a new but highly effective patients are treated with steroids, perienced this adaptation fi rsthand treatment. Also, have an age-appro- typically for up to a month or longer as his vision in low-light conditions priate patient consultant. We hired after the procedure on a tapering steadily improved during the postop- patient consultants who were in their schedule. Typically, we see them at erative months. Dr. Machat’s clinical 50s, because someone who’s in their one day, one week, and one month, director, Sondra Black, OD, reported 50s doesn’t want to talk to a 24-year- but of course we’d adjust that as nec- the same thing after her Kamra pro- old. They want to talk to someone essary.” cedure, he says. “She found that her who can actually relate to them and Dr. Hovanesian says that you may vision under low light improved over

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026_rp0218_f1_revised.indd 30 2/2/18 12:53 PM an entire year. When you talk to sci- “If and when an implant needs to Costa Mesa, California) when he entists like Jay Pepose, he says that be removed, the opportunity for en- started offering the Kamra. The this is exactly what occurs. I got to hancement to bring patients to em- costly imager is pretty much a must- live it. I was very surprised by it and metropia exists and we’ll tell them buy for Kamra surgeons, a fact that it didn’t make sense to me, but it’s we can do that, but we really have may have discouraged some from true,” he says. not had anyone ask for it,” he says, getting involved with Kamra. Dr. For all the potential benefi ts cor- adding that patients enjoy the near Machat also suspects that the sys- neal inlays can confer, the procedure component created by LASIK in the tem’s name at that time led to some also confers the risks that come with nondominant eye despite a slight loss surgeons declining to adopt inlays putting a foreign body into the eye. of distance visual acuity. because of a mistaken belief that “There is no such thing as a surgery the AcuTarget was only good for in- that has a zero complication rate. lay centration. “What they’re not re- Anytime we do something, there’s alizing is that I use it for Kamra only the possibility of an unexpected or 5 percent of the time; 95 percent of untoward outcome,” Dr. Vukich “There’s no such the time, I use it for refractive lens notes of his experience with the exchange, dry eye and other proce- Kamra. “One of the things we have thing as a reversible dures,” he says. seen is epithelial implantation: At the operation, but the Dr. Vukich also says that the HD time the implant was placed, a nest Analyzer is a great help with inlays, of epithelial cells was brought in with [Kamra] is clearly but that it its use isn’t limited to that the implant. We believe it occurs in removable.” area of practice. “I think that in the less than a fraction of 1 percent of setting of using inlays it’s quite valu- patients, and it’s easily fi xed. We can — John Vukich, MD able to have, but quite frankly, we simply rinse out the epithelial cells. use it far more widely than just for We’ve also had one patient in which implanting inlays,” he says. the implant was slightly irregular be- cause of a micro-fold. That was early Dr. Hovanesian was a consultant on in my experience, so there is a bit Check Your Technology for ReVision Optics and consults of a learning curve in terms of how to Dr. Machat notes that you need for AcuFocus. Dr. Machat is on the place the implant quickly, atraumati- the right tools to offer corneal medical advisory board for AcuFo- cally and in the location that you’re inlays. “You have to keep a real- cus and is a consultant for Viseo- looking for,” he says, “but inlay sur- ly high-quality femtosecond laser metrics. Dr. Vukich is a consultant gery is well within the skill set of any with a really tight raster pattern,” for AcuFocus, and was an investiga- anterior segment surgeon.” he says. “So that was one of the tor and part of the FDA regulatory One potential plus of corneal inlays advantages of using the Raindrop: team. is that they are strictly additive and You just needed to make a fl ap that removable. “There’s no such thing as was one-third of the central corneal 1. Holden BA, Fricke JR, Ho SM, et al. Global vision impairment due to uncorrected presbyopia. Arch Ophthalmol a reversible operation, but the inlay thickness, so you didn’t need pocket 2008;126:1731-39. is clearly removable. So to the extent software,” he says. 2. Moarefi MA, Bafna S, Wiley W. A review of presbyopia treatment with corneal inlays. Ophthalmol Ther 2017;6:55- that we can restore the native archi- Although he acknowledges that 65. tecture—with the exception of the obtaining the requisite technology 3. Food and Drug Administration. FDA summary of safety incision we’ve made—by removing for corneal inlays might be prohibi- and effectiveness data (SSED). PMA P120023. https:// www.accessdata.fda.gov/cdrh_docs/pdf12/P120023B.pdf. the implant, I think people fi nd that tively costly for surgeons not cur- Retrieved 1/17/2018. reassuring,” says Dr. Vukich, who rently offering LASIK, Dr. Vukich 4. Food and Drug Administration. FDA summary of safety and effectiveness data (SSED). PMA P150034. https:// reports that he has explanted one says that investment is minimal for www.accessdata.fda.gov/cdrh_docs/pdf15/P150034B.pdf. Kamra. Although patients who have those already offering it. “For a sur- Retrieved 1/17/2018. their refraction set for anisometropia geon who is already doing LASIK 5. Dexl AK, Jell G, Strohmaier C, et al. Long-term outcomes after monocular corneal inlay implantation for the surgical in anticipation of an inlay are left surgery, there is almost no startup compensation of presbyopia. J Cataract Refract Surg in that state if the inlay later comes cost to this,” he says. 2015;41:3:566–75. out, Dr. Vukich says that this has not Dr. Machat says he purchased 6. Limnopoulu AN, Bouzoukis DI, Kymionis GD, et al. Visual outcomes and safety of a refractive corneal inlay been problematic over the course the AcuTarget HD, the forerunner for presbyopia using a femtosecond laser. J Refract Surg of his experience with the Kamra. of the HD Analyzer (Visiometrics; 2013;29:1:12-18.

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0026_rp0218_f1_revised.indd26_rp0218_f1_revised.indd 3311 22/2/18/2/18 12:5412:54 PMPM Refractive Surgery REVIEW Cover Focus What’s Behind That SMILE

Edward Manche, MD, Stanford, Calif.

A look at patient here aren’t many procedures ate a side cut through which this len- that can install themselves ticule is removed. The removal of the selection, Talongside perennial stalwarts lenticule is what causes the change in PRK and LASIK as reliable, effective refraction. technique and methods to treat refractive errors, but In the United States, SMILE is ap- small-incision lenticular extraction has proved for the treatment of -1 D to -8 how SMILE shown the potential to do so. Approved D of myopia, with no more than -0.50 by the FDA in 2016, SMILE has been D of astigmatism and a manifest refrac- compares to shown to be safe and effective, both in tion spherical equivalent of -8.25 D, FDA trials and in international studies. which has been stable for a year. LASIK. If you’re curious about the nuts and bolts of the procedure, are about to Preop Screening and Exam perform your fi rst cases or are already performing SMILE but are open to When evaluating SMILE candi- some new tricks, this article is for you. dates, the selection criteria are similar In it, I’ll share my tips and techniques to those used for LASIK. for managing SMILE patients preop, I exclude patients with suspicious intraop and postop, and give you some corneal topography or thinner-than- idea where it stands when compared average corneas. I know that some to LASIK. SMILE surgeons feel SMILE has better biomechanical stability than A SMILE Refresher LASIK, and there have been some studies to that effect, but I still strive Since SMILE is relatively new on to maintain a minimum preop corneal the refractive scene in the United thickness of 500 µm. Some surgeons States, it might be helpful to describe think SMILE will expand the number the procedure. of patients you can treat by including What makes SMILE unique is that those with corneas that would be risky it’s an all-femtosecond laser refractive for LASIK, but I disagree. I think the procedure. The only laser currently indications will be virtually identical to able and approved to perform SMILE LASIK’s. Since you sever fewer cor- is the VisuMax femtosecond laser (Carl neal nerves, however, I believe that Zeiss Meditec). The surgeon uses the patients experience less dry eye with laser to cut a lenticule-shaped disc of SMILE than LASIK, and papers have tissue within the cornea and then cre- borne this out.1,2

32 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

0032_rp0218_f2.indd32_rp0218_f2.indd 3232 11/26/18/26/18 2:402:40 PMPM When selecting candidates, we’re Since SMILE is only approved for pa- somewhat limited in the United States tients with no or almost nonexistent in that we can only treat between -1 astigmatism, surgeons often ask about and -8 D. The machine will, however, performing other procedures before- allow you to treat up to -10 D, though hand to address cases with astigma- you’ll get a yellow warning light in- tism that’s beyond the approval range. dicating that the treatment is above Some surgeons might just perform an the approved range and that there’s AK, combining it with SMILE. But if not enough information on treatments you do this, I feel you’re shortchanging above that range. Internationally, how- the patient and the procedure. Astig- ever, SMILE has been shown to work matic SMILE should be approved in very well in myopia above -8 D. The the next six months or so in the United other aspect of the treatment ranges States. During that time, you have to you’ll notice is that you can’t program It helps to perform the anterior dissection ask yourself if you’d rather do an AK any astigmatism correction into the fi rst because the posterior side is tethered and combine it with SMILE or just down and keeps it stable during dissection. treatment, at least in the United States. wait until you can simply program the This makes patient selection a bit more VisuMax to do a compound astigma- challenging because, typically, many make sure that I also talk about LASIK tism treatment. The latter option is patients will have some degree of myo- and PRK. SMILE is a complementary better, in my opinion. If someone with pia and astigmatism. For instance, one procedure to LASIK and PRK, not a signifi cant astigmatism wants SMILE, eye might have 0.25 or 0.5 D of astig- competitive one. You shouldn’t bash I would just tell him to wait another matism, while the other has 0.75 D. one procedure, such as PRK, to build few months, or to have LASIK or PRK This limits the pool of patients who can up SMILE, because this can come now. I don’t think the results of com- undergo SMILE surgery at this time. back to haunt you should you need to bined AK and SMILE are going to In addition to the cornea and re- perform a PRK enhancement on the be as accurate as an all-laser SMILE fractive aspects, we also look for other SMILE patient. This goes the other procedure will be. signs of ocular health. In other words, way as well: Most of the patients who • VisuMax idiosyncrasies. It helps there should be no corneal staining, no come in for refractive surgery want to become familiar with the VisuMax epithelial basement membrane dys- LASIK because of the lack of pain laser, because it’s different from the In- trophy and no external eye disease like and the rapidity of visual recovery but traLase. The latter is a great machine blepharitis. If there’s meibomian gland may not know about SMILE. I inform that works well, but its suction is differ- dysfunction, we’ll also treat that preop. them that they’re also candidates for ent than the VisuMax’s. The IntraLase The preop discussion with the pa- SMILE, which has a lot of the same suction is very strong and can cause the tient needs to be handled a certain way. characteristics they’re looking for. patient’s vision to brown- or black out Some patients, having heard about It might also be worth informing the during the procedure, which means SMILE online or from the news, will patient that even though he’ll see well suction breaks are very rare with the come in and say, “I only want SMILE immediately after SMILE, the vision IntraLase. surgery.” These patients assume that won’t be as sharp as with LASIK, at With the VisuMax, on the other because SMILE is the newest surgery, least for approximately the fi rst week hand, the suction from the curved ap- it’s also the best one, an opinion that’s postop. It takes a little bit longer for planation cone that goes against the common when new technology arrives. vision to recover with SMILE. Most cornea is much lighter than with the Unfortunately, in many cases, these patients’ vision, however, is equivalent IntraLase. Because of this, you really gung-ho patients aren’t good candi- to what you’d get with LASIK after need to get used to the system. In fact, dates for the new technology for some about that fi rst week to the fi rst month. the company requires something in the reason, such as having too much astig- neighborhood of 30 to 50 LASIK fl aps matism. Also, the only reliable way we Procedure Pearls be performed with the VisuMax before currently have to enhance a less-than- it’ll even allow you to perform SMILE satisfactory SMILE outcome is PRK, Getting good at SMILE requires a with the device, just to help make you which patients need to be made aware knowledge of both the technology in- comfortable with its suction process. of. volved, and the art of manipulating the In my experience, this is very astute In light of these issues, I present fragile corneal lenticule. advice, since I’ve performed upward of SMILE in an evenhanded way, and I • Managing preop astigmatism. 2,000 VisuMax LASIK fl ap treatments,

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REVIEW Focus

and I’ve only had a couple of suction tethered in place during the dissection. breaks, all of which occurred in my fi rst If you save that tissue bridge for last, 50 cases. Since then, I’ve had none. you can sweep it aside to easily com- Because it has such light suction, then, plete the dissection. you have to be aware of patient move- Generally, once you’ve dissected ment or eye-squeezing, either of which the anterior portion, to access the pos- can break VisuMax suction quite easily. terior portion, look for some tension • Controlling patient movement. when you pull up a little on the poste- You’ll fi nd that, when you make fl aps or rior lenticule. The instrument will feel perform SMILE, as soon as you place snug under the posterior lenticule, and the speculum or attempt to put in any there will be no space like that between drops, you can tell if the patient is an the anterior lenticule and overlying eye-squeezer. If he is, tell him to relax cap. You may have trouble locating and not to clench his jaw or shoulders, After removing the lenticule, place it on the the posterior lenticule when you fi rst which may translate into eye-squeez- cornea and look for any missing pieces. begin performing SMILE surgery. If ing. Put your fi nger on the lid on top of you have trouble locating the posterior the speculum and note if the patient’s arate from the microscope that you portion, you sometimes have to move squeezing. If he is, just say, “I can feel use for the lenticule dissection and re- your instrument to fi nd an area where you squeezing. Please don’t,” and use moval. Once the cut is completed, you you can achieve access to the posterior your fi nger in this spot to monitor how bring the patient beneath that second lamellar resection. much squeezing is occurring, telling scope and then use a SMILE dissector After you’ve dissected out the lenti- him to stop when it happens. This ma- instrument to open the side cut, which cule, it’s critical to then pull it out and neuver also helps stabilize the head. is 5 mm in length. lay it on top of the cornea. Inspect it to It’s also important to make sure the With the side cut open, you use a make sure that it’s perfectly circular, patient is relatively comfortable and SMILE dissector to identify the ante- and that you haven’t inadvertently left doesn’t move his head or feet. Even rior and posterior aspects of the dis- any pieces in the interface. Laying it moving the feet can cause a move- section. To facilitate this, I’ll move the out like this will reveal any tears or ment of the head. I talk to the patients dissector to one side, for instance the retained lenticule material. If the tear throughout the procedure, informing temporal side on the right eye, and is small, you can go back into the inter- them what is about to happen and then identify the anterior-most plane. On face and tease out the remaining tissue. reassuring them as it does. “As the ap- the nasal side, I’ll go through the side (A feature of the VisuMax that’s helpful planation lens comes down on your cut and identify the posterior portion for this step is a light similar to that of eye, there’ll be a circle of white light enough so that I can put this spoon- a slit lamp.) with a green light in the center,” I say. shaped SMILE tissue separator in As you perform your initial cases, Once it applanates, the green light will afterward. Many companies offer you’ll find that visualization of the become sharply focused. “Look at the SMILE instruments. I started out with lenticule can be challenging. Usually, green light,” I say, engaging suction. SMILE instruments made by Malosa the anterior plane of the lenticule will Once suction is engaged, I tell him Medical (malosa.com). Malosa makes separate pretty easily, while the poste- not to worry about chasing the light a pack of single-use instruments exclu- rior one can be somewhat challenging around, but just keep looking straight. sively for the steps of the procedure. to find. Because of this, I’d strongly I inform the patient that it will take just Today, I use sterilizable SMILE in- recommend that those who are just under 40 seconds, but the fi rst 18 are struments of my own design made by starting out with SMILE spend time the most critical because that’s when ASICO (www.asico.com). with an experienced SMILE surgeon. the power cut is made. If you break You always want to separate the an- Alternatively, have one of the com- suction during that part of the cut, you terior lenticule fi rst. If you don’t, the pany’s representatives assist you with have to abort the procedure and switch procedure can become quite challeng- your fi rst cases. to PRK or LASIK. If you break suction ing because there will be nothing to • Dealing with low corrections. after the power cut, you can just restart tether the lenticule down. You dissect In contrast to LASIK, with SMILE the treatment with the anterior or the out the anterior lenticule fi rst, followed lower corrections are actually some side cut without a problem. by the posterior lenticule. Leave a of the trickiest ones. Though this may • After the cut. On the VisuMax, small bridge of tissue either nasally or sound counterintuitive, it makes sense there’s an operating microscope sep- temporally to help keep the lenticule when you think about the mechanics of

34 | Review of Ophthalmology | February 2018

032_rp0218_f2.indd 34 1/26/18 2:41 PM the procedure: The lenticules in a low plication such as epithelial ingrowth tralateral eye study in which one eye correction of, say, -2 or -3 D, are much with SMILE, which is, for the most gets LASIK and the other undergoes thinner than those in higher correc- part, treatable. SMILE. I plan to enroll 70 patients. tions, and are therefore more prone • Docking/suction issues. One Until that study’s complete, however, to tears. For example, a -1 D lenticule area where SMILE lags somewhat be- there are a few published studies, and could be about 25 µm thick, compared hind LASIK is in the margin for error the FDA approval data, to draw upon. to those in -8 or -10 D treatments, you have while creating the lenticule In the FDA data, though there were which are around 140 µm. Therefore, vs. creating a fl ap. Since this isn’t an no eyes preoperatively with an un- when you start out with SMILE, it’s excimer laser, there’s no auto-centra- corrected vision of 20/40 or better: probably best to start with corrections tion or auto-registration. Therefore, At the six-month visit, 99.7 percent in the -4 to -6 D range. This will yield it’s critical that you’re docked over the (327/328) and 87.5 percent (287/328) the most satisfying result for the pa- corneal vertex, which usually corre- of treated eyes saw 20/40 or better and tient and will be easier for you. sponds to the pupil center. This is be- 20/20 or better, respectively. In terms cause if you get a decentered docking, of predictability, 93 and 98.5 percent Possible Complications then you’re going to get a decentered achieved an MRSE within ±0.50 D lenticule, which can cause a number and ±1 D of the attempted correction, Many of the complications of of optical issues such as induced ab- respectively. The average preop myo- SMILE stem from the manipulation errations, degraded quality of vision, pia was -4.75 D (range: -1 to -10 D). of the lenticule. However, if you’re induced coma and astigmatism, and is On the complication side, 35 pa- careful, you can avoid them in most very diffi cult to correct. With LASIK, tients out of 336 (10.4 percent) re- cases. on the other hand, if your LASIK fl ap ported moderate or severe glare, and • Lenticule issues. If you’re not creation is off superiorly or inferiorly 20 (6 percent) had moderate or severe careful, you can perforate the overlying by 1 or 2 mm, for instance, and it’s a halos. By month 12, however, there corneal cap as you’re doing the dissec- 9-mm flap, you’ve got some margin were only four reports of the former tion, causing a tear. If you’re struggling for error. This isn’t the case with a len- (1.1 percent) and one of the latter to remove the lenticule, you can acci- ticule. Centration and not breaking (0.2 percent). At one year, 2.5 percent dentally tear the edge of the incision so suction are critical parts of the surgery. (8/311) of patients had lost a line of that it almost becomes more fl ap-like. • Handling enhancements. As best-corrected vision vs. preop; no pa- Some surgeons have recounted cases mentioned earlier, the current go-to tients lost two or more lines. The rest in which they couldn’t identify the an- procedure for a SMILE enhancement either improved or stayed the same. terior/posterior lenticule and couldn’t isn’t SMILE, but PRK. As my experience, and the FDA tri- dissect it out. In one such case, the If we need to perform an enhance- als, have shown, SMILE is a safe, effec- surgeon couldn’t remove the lenticule ment, we wait a minimum of three tive procedure. However, rather than completely—so he left the piece in the months, depending on the amount of being LASIK’s replacement, I believe cornea. The patient was dissatisfied initial myopia. For low myopes, such as it shines the brightest—and patients with the refractive results and eventu- -3 or -4 D, three months is usually suffi - and doctors are better served—when ally went to another surgeon, who end- cient. For a higher correction, however, it’s positioned as a complementary re- ed up extracting the remaining piece we might wait a little longer, maybe six fractive procedure. of lenticule a year later without any months. Though we haven’t had to do problem. The patient had a complete one of these yet, a number of surgeons Dr. Manche is the director of cornea recovery and was ultimately satisfi ed have shown that PRK works well. and refractive surgery at the Stan- with his SMILE surgery. There have ford University Eye Laser Center, and also been cases where this occurred, Follow-up and Results a professor of ophthalmology at the and the surgeon was able to complete university. He is a consultant for Aller- the dissection several months later For SMILE, I use the same follow- gan, Avedro, Shire, J & J Vision, Carl without incident. up schedule as LASIK: topical steroids Zeiss Meditec, Ocular Therapeutix and When compared with LASIK, I feel and a fourth-generation fl uoroquino- Avellino Labs. the fl ap vs. lenticule issues are com- lone, both q.i.d., for a week. I usually 1. Denoyer A, Landman E, Trinh L, Faure JF, Auclin F, Baudouin C. parable, but different: You can have see patients on day one, week one, one Dry eye disease after refractive surgery: comparative outcomes lenticule complications with SMILE month, three months and one year. of small incision lenticule extraction versus LASIK. Ophthalmology 2015;122:4:669-76. just as you can have fl ap complications In terms of results, I’m currently 2. Xu Y, Yang Y. Dry eye after small incision lenticule extraction and with LASIK. You can also get a com- performing my own prospective, con- LASIK for myopia. J Refract Surg 2014;30:3:186-90.

February 2018 | reviewofophthalmology.com | 35

0032_rp0218_f2.indd32_rp0218_f2.indd 3535 11/26/18/26/18 2:412:41 PMPM Refractive Surgery REVIEW Cover Focus Is There Still a Place For Manual LRIs?

Michelle Stephenson, Contributing Editor

Not only is there lthough toric IOLs and ex- astigmatism, so that we no longer do cimer laser photoablation are manual LRIs for high degrees of astig- a place for Asuperior to limbal relaxing inci- matism. We have better technology sions for treating moderate to severe now than we had in the past. Toric them, but some astigmatism, there is still a place for IOLs and excimer laser photoablation manual relaxing incisions for treating are our plan of action for most patients surgeons say smaller amounts of astigmatism, and with moderate to severe astigmatism. every surgeon should know how to When I’m performing cataract surgery they’re performing perform them. on a patient who has 1.5 D or more According to Eric D. Donnenfeld, of astigmatism, I feel very comfort- them more than MD, Ophthalmic Consultants of Long able offering him or her a toric IOL, ever. Island, manual LRIs are as vibrant and whether it be a monofocal lens, ex- important to optics and ophthalmology tended-depth-of-focus, or a multifocal as they have ever been. “The reason or accommodating IOL.” for this is that, as patient expectations However, when the cylinder drops have increased, the management of down to 1 D or less, Dr. Donnenfeld residual astigmatism associated with feels that the advantages of a femto- cataract surgery has become of par- second laser are signifi cant. “I like to amount importance,” he says. “The combine the advantages of femtosec- previous generation of LRIs were per- ond laser technology with a femto- formed to debulk the patient’s astig- second LRI so that the patient can matism. The plan today is to eliminate have the perfect capsulotomy and the All imaes: Kevin M. Miller, MD

Figure 1. (A) This patient suffered trauma, resulting in a white intumescent cataract, iris damage and posterior synechiae. A femtosecond laser phaco incision was placed in the steep corneal meridian to deal with astigmatism of less than 1 D. (B) The appearance of the eye after the surgery.

36 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

036_rp0218_f3.indd 36 1/26/18 2:10 PM lens disassembled. However, sweet spot,” he says. “I like postoperatively, I routinely doing my manual LRIs at the continue to perform manual slit lamp because it’s an easier LRIs for patients who have procedure for the patient. One residual astigmatism. The incision is all that’s required, amount that’s tolerated has and I use a pre-set diamond gone down dramatically as knife at 600 µm depth with a patient expectations have in- curved interface that hits the creased. We used to tolerate cornea. This creates a deeper, 1 D of residual astigmatism, more regular incision. So, for but the current conventional patients whose expectations wisdom is 0.5 D. However, Figure 2. An Alcon LenSx femtosecond laser in the process of have not been met and who making corneal incisions. The phaco incision was placed on the I’ve seen many patients who steep corneal axis in a superotemporal meridian to correct less have residual astigmatism, will not even tolerate 0.5 D than 1 D of corneal astigmatism. rather than bringing them based on their visual expecta- back for an excimer laser ab- tions and the knowledge that, lation or a femtosecond LRI, with a manual LRI, I can reduce the corneal axis, you get the full effect of these small amounts of cylinder are cylinder very commonly to 0.25 D or the lens. However, if it’s 3 degrees, 5 easily treated with manual LRIs. The less,” he adds. degrees, or 10 degrees off of that, you visual rehabilitation is almost immedi- start losing power, and you rotate the ate, and for patients who are receiving Small Amounts of Astigmatism axis of residual astigmatism to some a premium IOL, specifi cally multifo- new location, which might be harder cal and extended-depth-of-focus, the According to Kevin M. Miller, MD, for patients than what they were used quality of vision and the added reading from UCLA, “For high amounts of to before the surgery. So, toric lenses vision that’s obtained by reducing this astigmatism, nobody argues the ben- aren’t perfect. There are issues on both 0.5 D or so of astigmatism can be very efits of a toric lens over relaxing in- sides. When we’re dealing with small dramatic. It can turn a dissatisfi ed pa- cisions,” he says. “But when you get amounts of astigmatism, generally, we tient into a very grateful postoperative down to smaller amounts, you can still only need to make it a little bit better, patient.” make a compelling case for why you and you can almost always do that with a might want to do a relaxing incision relaxing incision,” he explains. Techniques instead of implanting a low-power toric “As time has gone on, and as toric lens. A benefit of toric lenses is that lenses have nibbled a larger portion of According to Dr. Miller, many sur- the power is going to be uniform from the astigmatism market away from in- geons believe that LRIs must be per- lens to lens, which is not always the cisions, I think we’ve seen a resurgence formed in pairs, one on each side of the case with LRIs. If you make the exact of incisions to touch up postoperative cornea. That simply isn’t true, he says. same incision in 100 different corneas, refractive errors,” he adds. “So, if a pa- “You can perform a relaxing incision on you’re going to get a spread of effect tient has mixed astigmatism, such that just one side of the cornea,” he notes. with 100 slightly different outcomes. the spherical power of the eye is dead- “Eighty percent of my astigmatism So, the predictability of relaxing inci- on and the spherical power of the lens management at the time of cataract sions is just not as good as with the implant is good, but there is residual surgery is simply moving my phaco torics. However, toric IOLs are not mixed astigmatism, either right after incision onto the steep axis. If a patient perfect, either.” surgery, a couple of weeks later, a year has 1 D or less of corneal cylinder, I If the toric lens sits in the presumed later, or five years later, the surgeon will just place the phaco incision on effective lens position, then the toric can touch up those mixed astigmatisms the steep axis, and I can get that down power calculation is accurate. But if it with relaxing incisions and get a nice to 0.5 D or so without a matching inci- sits a little anterior or posterior to the result.” sion on the other side, and without a ELP, then its calculated power is not Dr. Donnenfeld says he’s performing toric lens. So, 75 to 80 percent of my its effective power. So, there is variabil- increasing numbers of LRIs for smaller astigmatism management is still just a ity of toric lens power based on vertex and smaller amounts of astigmatism. single relaxing incision instead of a pair distance, but there is also variability “The majority of LRIs that I perform of incisions. So, in a sense, it’s still the of effect based on axis alignment. “If today are for 0.5 D to 1 D of residual driving force of astigmatism manage- the lens is sitting exactly on the correct cylinder, with 0.5 to 0.75 D being my ment, at least for my practice, and I

February 2018 | reviewofophthalmology.com | 37

036_rp0218_f3.indd 37 1/26/18 2:35 PM 036_rp0218_f3.indd 38 Miller concludes. one ofmymostimportanttools,”Dr. sons, LRIswork,andtheywillremain times willrotateoff.So,foralotofrea- rotate offthataxis.Toric lensessome- make themontherightaxis,theydon’t ing incisionsdon’t rotate;whenyou small amountsofastigmatism.Relax- they’re somethingthatcancorrect surgery,” headds. mean moretimecalculatingbeforethe patient moremoney, andit’s goingto incision. But,that’s goingtocostthe ing bymakingtheirtemporalcorneal in with,pluswhateverthey’reinduc- to nullifywhateverthepatientcomes rotate ittowhateveraxisisnecessary nea. “Then,they’lluseatoriclensand sit onthetemporalsideofcor- ample, somesurgeonsalwaysliketo to operateonthesteepaxis.Forex- moving theirchairandmicroscope many surgeonsdon’t feelcomfortable laser-assisted cataractsurgery.” the riseinpopularityoffemtosecond practices. Thisisespeciallytruewith suspect that’s probablytrueforalotof 38 several reasonsforthis.The most ob- should beembracing.Andthere are if wehaven’t embracedit yet, we actually are.It’s askillandanartthat, forgetting howusefulmanualLRIs ing astigmatickeratotomieswithout refractively mindedshouldbeoffer- sultants, “allcataractsurgeonswhoare who isinpracticeatVirginia EyeCon- A LostArt “I likerelaxingincisionsbecause However, Dr. Millernotesthat According toElizabethYeu, MD, REVIEW |

Focus Cover Review ofOphthalmology

Refractive Surgery | February2018 have, no matter what other treatment have, nomatterwhatothertreatment manual LRIisareallyimportant skillto agrees. “Ithinkbeingabletoperform a ton EyeAssociatesinMassachusetts, the manualLRI,”sheexplains. should notforegotheartformthatis So, therearemanyreasonswhywe improve theoutcomeforsurgeon. monofocal IOL.Thiscanreallyhelpto rometry callsforastandard,non-toric implanted, orifintraoperativeaber- where thetoricIOLcouldnotbe include acomplexcataractprocedure LRIs,” sheexplains.“Suchscenarios stand andbecomfortablewithmanual it’s importantforsurgeonstounder- instead bebestservedwithanLRI, not begettingatoricIOL,butwould demonstrates thatthepatientshould thing happensintraoperativelythat against-the-rule astigmatism. with anymorethan0.70Dofanterior entially offersatoricIOLtopatients with-the-rule astigmatism,butprefer- til sheseesatleast1.4Dofanterior offer thesepatientsatoricIOLun- astigmatism. Specifi affects theoverallrefractivecorneal tion ofposteriorcornealcurvature levels ofastigmatism.” ital, cost-effi cient waytoreducelower manual LRIsareaverynice,low-cap- have betteruncorrectedvision,and “There aremanypatientswhocould al astigmatismcorrection,”shesays. IOLs startat1Dormoreofcorne- ity uncorrectedvision,becausetoric enough toreallygivethemgreatqual- predictably reducetheastigmatism Jeremy Z.Kieval,MD,fromLexing- “Lastly, inthosecaseswheresome- Dr. Yeu explainsthatthecontribu- incision was meridian. placedsuperonasally inthesteepcorneal withimplantationofamultifocalIOL. cataract surgery The phaco Figure 3. This eye underwentstandard femtosecondlaser-assisted a very nice way to a verynicewayto lower range,itis tism inthe1Dor who haveastigma- for thosepatients vious oneisthat, cally, shedoesn’t manual LRIs,”hesays. same istrueforbeingabletoperform in handyeveryonceawhile.The cataract extractionisaskillthatcomes how todophaco,butextracapsular do extracapsurgery. Everybodyknows new surgeonsaren’t learninghowto been sayingforthepast15yearsthat your laserisn’t working.Surgeonshave go onwithyourdayintheeventthat It’s anice skilltohavebeable ever, whatifyourlasergoesdown? performing LRIsinmostcases.“How- lasers areprobablythebestchoicefor relaxing incision.” toric lensorafterafemtosecondlimbal they mayhaveafterimplantationofa the patient’s residualastigmatismthat do intheoffi ce attheslitlamptoadjust surgery toaminorprocedurethatIcan operating roomatthetimeofcataract procedure thatIexclusivelydidinthe offi I usemanualLRIsthemostisin ual astigmatism.Forme,theplacethat pecially formanagingapatient’s resid- skill thatallsurgeonsshouldhave,es- options existoutthere,”hesays.“It’s a dure,” hesays. of-pocket foracostlyastigmatic proce- they aren’t inthepositionto payout- if Ifeelit’s intheirbestinterestandif my procedureatnocosttothepatient I routinelybundlemanualLRIsinto to payapremiumforcataractsurgery, tients whodon’t wanttoorcan’t afford a betterresult,andspecifi cally forpa- For thosepatientswhowanttohave manual LRIsinasubsetofpatients. by theFDA,mayreduceneedfor justable lens,whichjustgotapproved the foreseeablefuture.“Thelight-ad- will stillbearoleformanualLRIs The Future Dr. Kievalbelievesthatfemtosecond Dr. Donnenfeld believes thatthere ce. I have been transitioning from a ce. Ihavebeentransitioningfroma 1/26/18 2:36 PM ONSITE REGISTRATION AVAILABLE

SAVE THE DATE OphthalmologyUpdate FEBRUARY 17-18, 2018 • CARLSBAD, CALIFORNIA An interdisciplinary faculty of ophthalmic subspecialists will review the continuing progress in Cataract and Refractive Surgery, Glaucoma, Retina, Neuro-Ophthalmology, Pediatric Ophthalmology, Ocular Surface Disease, Cornea and Oculoplastics.

LOCATION KEYNOTE SPEAKER Cape Rey Carlsbad, A Hilton Hotel Larry Smarr, PhD 1 Ponto Road, Carlsbad, CA UCSD SPEAKERS P: (760) 602-0800 Natalie A. Afshari, MD, FACS Limited rooms reserved at $209/night. PROGRAM TIMES Please visit registration site for Andrew S. Camp, MD reservation information. Saturday, February 17 Daniel L. Chao, MD, PhD PROGRAM CHAIRS 8:00am — 5:00pm William R. Freeman, MD Reception to follow Michael H. Goldbaum, MD Don O. Kikkawa, MD, FACS Weldon W. Haw, MD Robert N. Weinreb, MD Sunday, February 18 8:00am — 12:15pm Chris W. Heichel, MD DISTINGUISHED Bobby S. Korn, MD, PhD, FACS INVITED SPEAKERS Eric D. Nudleman, MD, PhD Nisha Acharya, MD Shira L. Robbins, MD, FAAO, FAAP C. Gustavo De Moraes, MD, MPH Peter J. Savino, MD Audrey C. Ko, MD Derek S. Welsbie, MD, PhD Daniel M. Schwartz, MD Kang Zhang, MD, PhD Jonathan C. Song, MD, MBA Benjamin Y. Xu, MD, PhD FOR MORE INFORMATION www.reviewofophthalmology.com/Update2018 Email: [email protected] Phone: 855-851-9964 Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Amedco and Postgraduate Health Education, LLC (PHE). Amedco is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement Amedco designates this live activity for a maximum of 11.25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity

Jointly provided by Shiley Eye Institute Review of Ophthalmology® UC San Diego Glaucoma Management

REVIEW Edited by Kuldev Singh, MD, MPH, and Peter A. Netland, MD, PhD

Supplements & Glaucoma: Advising Your Patients Given the popularity of questionable “alternative” treatments, your patients are counting on you to set them straight.

Lisa S. Gamell, MD, Tampa, Fla.

oday, Americans often take Related Eye Disease Study found that with increased cortisol, which in turn T vitamins, herbs and other sup- a combination of antioxidants and zinc increases IOP. A study he published plements—and they’re usually aware was able to reduce the progression did find lower serum thiamine in of many more that they may not actu- of disease in macular degeneration glaucoma patients.2 However, vitamin ally be taking. So it’s no surprise that patients with intermediate and large B1 didn’t signifi cantly lower IOP, and our patients sometimes ask our opin- drusen by 25 percent,1 so it is possible unfortunately, the study wasn’t well- ion on the value of these supplements, to find something in the world of designed. Other evidence suggests in particular how they may or may not complementary and alternative medi- that B1 levels may not impact glau- impact glaucoma. Furthermore, with cine that can help address eye disease. coma; alcoholics, for example, tend to marijuana becoming legal in more In glaucoma, we just haven’t yet found be defi cient in vitamin B1, but there’s and more states, questions about its the perfect mixture. The reason for no correlation between alcoholism reputed ability to lower intraocular that may be, in part, that glaucoma is and glaucoma. pressure are likely to come up as well. actually a cluster of related diseases. • Vitamin C. The evidence for Our patients look to us for evidence- Treating it may ultimately involve vitamin C’s impact on glaucoma is based information about these addressing both pressure issues and mixed. One study found that intra- substances. Here, I’d like to review neuroprotective issues. venous vitamin C lowered IOP 20 a little bit of what the studies to date Vitamin supplements that have percent over two hours; it does appear have shown, to offer some guidance been posited to have an effect on to have a significant osmotic effect, regarding what you might want to say glaucoma include B1, B3, B12, C, similar to mannitol.3 However, IOP to your patients when these questions A and E. The chart on the facing climbs back up over 10 to 12 hours, and arise. page shows some of the studies, pro it’s not really practical to give someone and con, concerning fi ve of the most IV vitamin injections. Other studies, The Value of Vitamins commonly taken vitamins. Notably, looking at vitamin C supplements, the results of different studies are didn’t show much of a change in It’s not unreasonable to believe that often contradictory. pressure.4,5 And while vitamin C has a supplements such as vitamins could A few observations: benign reputation, it can cause kidney impact the progression of glaucoma. • Vitamin B1 (thiamine). Edward stones and gastrointestinal upset, and Doctors dealing with age-related Asregadoo, MD, theorized that B1- it should be avoided in those with a macular degeneration have already deficient patients might be more glucose-6-phosphate dehydrogenase demonstrated the potential of this prone to glaucoma. He noted that (G6PD) defi ciency, B-thalassemia or approach. As we all know, the Age- low levels of vitamin B1 are associated hemochromatosis.

40 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

040_rp0218_gm.indd 40 1/26/18 4:24 PM Vitamin Supplements and Glaucoma Vitamin Proposed Action Results: Pro Results: Con Side Effects

B1 Low B1 increases cortisol Lower serum thiamine B1 not shown to lower IOP None (thiamine) level, which increases IOP found in glaucoma patients in study2 (Asregadoo, 1979)2 (n=38)2 C Creates osmotic gradient and IV vitamin C 20% lowered Oral vitamin C, 2 gm/day: no Kidney stones; (ascorbic acid) lowers IOP. May be IOP 20% over two hours effect (Linner)4 GI upset; neuroprotective (Virno)3 Oral vitamin C, 4.5 gm/day: Avoid in G6PD, B-thalassemia, no change (Fishbein)5 hemochromatosis A Antioxidant properties protect Protects photoreceptors in No association between Hair loss; fatigue; increased (retinol) retinal ganglion cells AMD (AREDS)1 serum levels or intracranial pressure; cirrhosis. supplementation and POAG Beta carotene increased lung prevalence (Wang)6 cancer in smokers E Antioxidant properties protect May lower serum lipid No association between Increased bleeding (alpha retinal ganglion cells peroxidation products in serum levels or perioperatively, or if patient is tocopherol) glaucoma patients (Birich)7 supplementation and POAG on anticoagulants prevalence (Wang)6 B12 Neuroprotective: Improved GVF function with No baseline B12 levels None (cobalamin) Defi ciencies cause optic oral B12 (Azuma)8 noted in either study. Azuma neuropathy Less GVF deterioration with study8 only had nine months oral B12 (Sasaki)9 follow-up

• Vitamin A (retinol). As an anti- deficiencies in B12 are associated protection than either one alone. So oxidant, vitamin A might be expected with optic neuropathy. Two studies in vitamin B3 we have the potential to protect retinal ganglion cells, and found visual fi eld improvement with for an agent that not only has a the AREDS study did fi nd evidence vitamin B12 supplementation,8,9 but neuroprotective effect but can also that it protects photoreceptors in no baseline B12 levels were done in continue having that protective effect macular degeneration patients. these studies, and they had very short in the presence of elevated pressure. However, a study by Sophia Wang, follow-up. The idea that nicotinamide may have MD, found no association between Other supplements have produced benefi cial effects has been proposed vitamin A supplementation or serum interesting results in animals and in for further investigation in humans.11 levels and primary open-angle glau- in vitro studies. Vitamin B3 (nicotina- So far, however, this has only been coma prevalence.6 Meanwhile, retinol mide), for example, may be neuro- shown in animal studies. can have side effects including hair protective. One animal study reported One of the main problems with loss, fatigue, increased intracranial in Science10 found that vitamin B3 vitamin studies is that studies tend pressure and cirrhosis. could help to mitigate mitochondrial to involve very small numbers of pa- • Vitamin E (alpha tocopheral). dysfunction, which has been linked tients, and a lot of the reports have Vitamin E does have antioxidant to retinal ganglion cell damage and been anecdotal. The reality is that properties, and one study found that death. In this study, mice were fed since the U.S. Food and Drug Admin- it may lower peroxidation products a supplement equivalent to 2.5 istration doesn’t need to approve any in glaucoma patients.7 However, the grams a day in humans; it prevented of these agents, there’s no incentive previously mentioned study by Dr. the structural and functional loss of for large studies to be conducted, the Wang6 found no association between ganglion cells and nerve axons, and the way there might be with drugs that vitamin E and glaucoma prevalence, effect persisted, even with elevated need FDA approval. As a result, very and vitamin E can potentially cause pressure. Furthermore, intravitreal few large, controlled studies have increased bleeding perioperatively, as injections of a gene that produces been done. well as in patients already taking an nicotinamide protected 70 percent of There’s also another significant anticoagulant. mice from glaucomatous damage for problem: Many of these studies are • Vitamin B12 (cobalamin). B12 12 months. In addition, combining done in vitro, where, for example, is neuroprotective, and we know that the two approaches provided more the agent may protect ganglion cells.

February 2018 | reviewofophthalmology.com | 41

0040_rp0218_gm.indd40_rp0218_gm.indd 4141 11/26/18/26/18 4:254:25 PMPM Glaucoma

REVIEW Management

Herbs and Glaucoma

Herb Proposed Action Results: Pro Results: Con Side Effects Gingko Potent antioxidant effects 40 mg p.o. t.i.d. increased Found no change in blood Increased risk for (Gingko biloba inhibit platelet activating ocular blood fl ow with color fl ow with Heidelberg Retinal hemorrhage in patients with extract EGb 761) factor and glutamate- doppler imaging Flowmeter (Ritch)15 amyloid, hypertension induced neurotoxicity (Chung, Harris)13 No effect on visual fi eld or or on anticoagulants improved HVF in NTG contrast sensivity (Guo)16 (Quaranta)14 Bilberry Anthocyanidins have Ameliorated NMDA damage in No studies in humans May interact with ASA and (vaccinium antioxidant effects that mouse model showing effects on IOP or warfarin. myrtillus) protect against ischemic (Matsunaga)17 visual function; GI upset; icterus; cachexia; reperfusion and Reports of improved night anemia neurotoxicity vision among WWII pilots were anecdotal Forskolin Adenylate cyclase- Topical 1% forskolin reduced Hyperemia; Oral preparations: (coleus forskohlii) mediated reduction of IOP and aqueous fl ow in Tachyphylaxis limited long- Arrythmogenic; aqueous fl ow rabbits, monkeys, humans term effi cacy Promotes androgen activity (Caprioli)18 on prostate cancer cells

But when a person ingests a supple- stimulating increased quantities of challenges when studying gingko’s ment, it has to go through all of the mitochondria.13 Unfortunately, when effect on blood flow is that we still metabolic processes in the body, so a person ingests co-enzyme Q or res- don’t have agreement on the best way the potency could be significantly veratrol in supplement form, the ef- to measure ocular blood fl ow, making diminished by the time it gets to the ficacy may be dramatically altered it difficult to draw any conclusions nerve cells. That makes it diffi cult to by the metabolizing process. Clini- about how helpful gingko actually know what the proper dose should be cal trials in humans could do a lot may be. for humans. to pin down the quantities and con- One other important consideration centrations required to produce simi- when suggesting that a patient try Other Supplements & Nutrients lar effects in our patients. gingko: Gingko increases the risk of A few herbal supplements are also bleeding. For that reason, you have The problem of potency following believed to have positive effects on to make sure your patient is not on ingestion is an issue with two non- the eyes and glaucoma. The chart warfarin, aspirin or any other blood vitamin supplements that have above shows some of the data relating thinners, because your patient could shown promise with glaucoma: co- to three popular herbal supplements be prone to getting pretty severe enzyme Q and resveratrol. These that sources on the Internet claim will hemorrhages. have been shown to reduce mito- help treat glaucoma. • Bilberry (vaccinium myrtillus). chondrial susceptibility in vitro, and I A few observations about these The bilberry plant is a cousin of the believe they show promise for neuro- three herbal supplements: blueberry. In World War II, fighter protection. • Gingko biloba. This is a well- pilots took bilberry to increase their One study found that topical mi- known antioxidant used widely in night vision, but to date, no study has celles of co-enzyme Q10 with vita- Europe to treat breathing problems been done to confi rm that this effect min E d- -tocopheryl polyethylene and Reynaud’s phenomenon, which is is real. As an anthocyanidin, bilberry glycol 1000 succinate, twice a day, a vascular disorder. Gingko is known has a very potent antioxidant effect significantly reduced the number to inhibit glutamate cytotoxicity, that can protect against ischemic of apoptotic retinal ganglion cells which leads to ganglion cell death, reperfusion and neurotoxicity, and three weeks after induction of and it’s been shown to increase blood it’s been shown to decrease retinal ocular hypertension. Furthermore, flow.14,15 However, these were very ganglion cell damage in a mouse the effect was independent of IOP.12 small studies, and there were a couple model.18 However, no studies in hu- Another study found that resveratrol of contrasting studies that found no mans have shown any effect on IOP retarded apoptosis of RGS’s in vitro effect on visual fi eld or contrast sen- or visual function. Bilberry can also and decreased the level of caspace-3 sitivity, as well as one that found no interact with aspirin and warfarin and (a marker of apoptotic events), while change in blood fl ow.16,17 One of the potentiate bleeding; and it has been

42 | Review of Ophthalmology | February 2018

0040_rp0218_gm.indd40_rp0218_gm.indd 4242 11/26/18/26/18 4:254:25 PMPM associated with gastrointestinal upset, only lasted three to four hours. icterus, cachexia and anemia. It’s also difficult to evaluate these • Forskolin (coleus forskohlii). studies relative to today’s marijuana This herb has been shown to lower use because marijuana potency is IOP in rabbits, monkeys and humans difficult to verify. In the early stu- by reducing aqueous fl ow. This was dies, individuals were smoking 2% fi rst demonstrated back in the mid- marijuana cigarettes; today the con- 1980s.19,20 However, further studies centration of THC in a marijuana were abandoned because forskolin cigarette may be much higher. caused significant hyperemia and A few years later, Keith Green, tachyphylaxis. Furthermore, after PhD, did similar studies using oral a month or two the pressure would Although early studies suggested that ingestion (e.g., eating marijuana 25 shoot back up, so there wasn’t a lot of marijuana may reduce IOP for a few hours, brownies). The results were mixed; long-term promise. Oral preparations a host of side effects and practical in some patients this lowered IOP, are available, but when you take concerns make its use as a glaucoma but in others it didn’t. In any case, oral forskolin orally it doesn’t have any treatment controversial at best. ingestion requires larger quantities effect on IOP. Downsides include of the drug to produce the same that forskolin is arrythmogenic, and One of the take-home messages effect, which makes sense because it can promote androgen activity on here is that although we often hope the drug is being taken in through the prostate cells in patients with prostate to get relief from supplements in gastrointestinal tract where it must be cancer. pill form, there may be an advantage metabolized by the liver, etc. That’s Some nutrient-rich foods show pro- to ingesting beneficial nutrients in going to decrease the potency and mise for impacting glaucoma pro- their natural dietary form. Other availability of any active compounds. gression. The Osteoporotic Fractures pro-nutrients in these vegetables Of course, marijuana can have nu- Research Group found that patients and fruits may also be contributing merous side effects. These include who ate three or more servings of protective effects. ocular side effects such as conjunctival fruit such as peaches or oranges, or hyperemia, decreased lacrimation, fruit juices, per day were 79 percent Medical Marijuana diplopia, impaired accommodation, less likely to have POAG. In addition, photophobia, nystagmus and bleph- those who ate more than one serving The herb patients most often ask arospasm. Systemic side effects in of collard greens or kale, which are about, not surprisingly, is marijuana. the short term may include increased nitrate-rich, leafy green vegetables, Medical marijuana is currently legal pulse, orthostatic hypotension, and per week decreased their odds of in 30 states, including the District of course, euphoria.26 Over the long having POAG by 57 percent.21,22 The of Columbia, and recreation- term, side effects may include emphy- Nurses Health Study and Health Pro- al marijuana is legal in a sema-like lung changes, decreased fessionals Follow-up Study found handful of states, most recently immune function, decreased cognitive that a greater intake of nitrate-rich California (as of January 1, 2018). function and potential alterations in foods and leafy green vegetables The interesting thing about mari- the growth of a fetus. (It would be decreased the risk of POAG by 20 to juana is that it’s a Schedule I con- helpful to conduct long-term studies, 30 percent.23 These are large, well- trolled substance, while opioids, but as long as marijuana remains a designed population studies. Gran- amphetamines and cocaine are Sche- Schedule I agent, that’s unlikely to ted, they were large cohort studies dule II. That means that, unlike mari- happen.) that relied on statistical analysis, and juana, they’re available for research. Encouraging patients to smoke the data was based upon patient self- The original studies on marijuana marijuana to address glaucoma is reporting, so they could contain an were done back in the 1970s.24 controversial at best. Smoking inher- element of bias. It’s also possible that Those studies, using a small sample ently carries some risk for emphysema individuals eating large quantities of participants, showed a signifi cant and lung cancer, along with the other of these foods may have a healthier reduction in IOP (25 to 30 percent) aforementioned side effects. The lifestyle overall, and that might be in 65 percent of patients. However, orthostatic hypotension issue may contributing to their reduced POAG. participants’ eyes got red, tear pro- also be significant, because of the Nevertheless, the statistics are pretty duction decreased, pupils got smal- likelihood that the drug is decreasing impressive. ler, and the decrease in pressure blood fl ow to the optic nerve, which

February 2018 | reviewofophthalmology.com | 43

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REVIEW Management

could be damaging. The CNS side reasons, have not been investigated. appears that it’s not completely free effects are problematic, especially of the euphoric effects. Some patients for older patients. Moreover, current Managing Patient Questions complain that they still experience topical medications usually have a effects such as lightheadedness or better efficacy profile for lowering Patients ask me about smoking confusion—while other patients are IOP. For all of these reasons, both the marijuana all the time; they want not bothered at all. (Hopefully the American Academy of Ophthalmology me to prescribe it for them. If you research into topical cannabinoids will and the American Glaucoma Society haven’t already encountered this, you bear fruit, thus taking any systemic currently do not recommend the use probably will. side effects off the table.) of marijuana to treat glaucoma. Here are a few strategies that may A promising approach in the future help you manage this situation when Playing It Safe may be the use of cannabinoids, the it arises: active compounds found in mari- • Be aware of the marijuana laws Given the popularity of supple- juana, which are receiving research in your state. Use of marijuana, even ments and marijuana today, it’s attention. Cannabinoids such as for medical reasons, is subject to law. essential that we be prepared to help delta9-THC and cannabidiol have To keep yourself and your patients out our patients navigate the rational use been shown to decrease IOP; they of trouble, do your homework about of these substances. We have to be act on cannabinoid receptors in the the legal ramifi cations in your state. ready to educate patients on their trabecular meshwork and increase • Be ready with an answer be- effi cacy and side effects. A few points aqueous outfl ow, and they also have fore your patients ask questions. I worth making: neuroprotective qualities. One explain to my patients that so far it’s not • Patients should be careful with study of WIN55212-2 found that clearly defi ned how marijuana should any of these supplements because it decreased IOP 20 to 30 percent, be used to treat glaucoma. Even even if they may potentially help, achieving maximum effect within 60 though it’s approved for glaucoma no one knows the proper dosage. minutes, although the effect did not treatment here in Florida, there are no The reality is, these treatment pos- last long.27 guidelines. In addition, the American sibilities haven’t been seriously stud- Some more recent research in- Academy of Ophthalmology and ied, so we’re making choices based on volving THC prodrugs such as THC- American Glaucoma Society do not minimal information. Val-HS has been more promising. advocate its use for treating glau- • Be careful about the purity of Coupling the drug with cyclodextrins coma. For these reasons—among the substance in question. Many and surfactants helps to increase others—the majority of doctors herbs are sold mixed with other herbs, solubility, so there’s more availability I know won’t prescribe it. (I don’t, and some individuals can have pretty and better penetration through the either.) dramatic side effects from those cornea. In a rabbit model this pro- • Educate and inform interested additional herbs. duced a better IOP lowering than patients regarding the efficacy, • Do your homework before timolol, although it had a shorter side effects and drug interactions proceeding. Your patients should talk duration of action, similar to pilo- associated with marijuana use. to their internist if they’re planning on carpine.28 Most interested patients have little, using supplements, to make sure they The main point is, while smoking if any, idea about this aspect of mari- don’t interact with any prescription marijuana isn’t something that we uana use. It’s worth pointing out that drugs they may be taking. Some as ophthalmologists currently stand while marijuana may lower IOP in the supplements will interact with blood behind, cannabinoid agents may have short term, in the long term it may do thinners, or may exacerbate other the potential for ocular penetration them more harm than good. problems like prostate cancer or without the potential for side effects • Consider prescribing an oral gastrointestinal issues. While some such as orthostatic hypotension cannabinoid like Marinol (dronab- supplements may be helpful, they are and euphoria. In the meantime, inol) instead. Marinol has been used not totally benign. the potential for benefits from the for decades in cancer patients to treat • Encourage a healthy diet occasional adjunctive use of marijuana nausea and other gastrointestinal side with antioxidant and nitrate- in addition to prescribed glaucoma effects of chemotherapy. The few rich foods including citrus fruits, treatment regimens, and the effects times I’ve prescribed it for patients, peaches, salad, kale and collard of marijuana in glaucoma patients it’s had a modest effect on IOP, low- greens. These foods not only limit who regularly use it for nonmedical ering it 10 to 15 percent. Notably, it the possibility of side effects, they

44 | Review of Ophthalmology | February 2018

0040_rp0218_gm.indd40_rp0218_gm.indd 4444 11/26/18/26/18 4:254:25 PMPM have some of the most impressive intake and serum levels in a population-based sample of the A randomized, crossover clinical trial. Invest Ophth Vis Sci United States. Eye 2013; 27:4:487-494. 2014;55:110-116. supporting evidence in the literature. 7. Birich TV, Birich TA, Marchenko LN: [Vitamin E in multiple- 18. Matsunaga N, et al. Bilberry and its main constituents have Citing some of the statistics found modality treatment of primary glaucoma patients]. Vestn Oftalmol neuroprotective effects against retinal neuronal damage in vitro 1984;102:10–3. and in vivo. Mol Nut Food Res 2009;53:7:869-77. in the research may surprise and 8. Azumi I, Kosaki H, Nakatani H. Effects of metcobolamin 19. Caprioli J and Sears M. Forskolin lowers intraocular pressure impress your patients. (Methycobal) on the visual fi eld of chronic glaucoma—a in rabbits, monkeys, and man. Lancet 1983;1:958-960. multicenter open study. Folia Ophthalmol Jpn 1983;34:873–878. 20. Caprioli J, et al. Forskolin lowers Intraocular pressure by 9. Sasaki T, Murata M, Amemiya T. Effect of long-term treatment reducing aqueous infl ow. Inves Ophthalmol Vis Sci 1984;25:268- Dr. Gamell is an associate professor of glaucoma with vitamin B-12. Glaucoma 1992;14:167–170. 277. 10. Williams PA, et al. Vitamin B3 modulates mitochondrial 21. Coleman AL, Stone KL, Kodjebacheva G, et al. Glaucoma of ophthalmology at the University vulnerability and prevents glaucoma in aged mice. Science risk and the consumption of fruits and vegetables among older of South Florida Health Morsani 2017;355:756-760. women in the study of osteoporotic fractures. Am J Ophthalmol 11. Williams PA, Harder JM, John SW. Glaucoma as a metabolic 2008;145:6:1081–1089. College of Medicine, and Glaucoma optic neuropathy: Making the case for nicotinamide treatment in 22. Giaconi JA, et al. The association of consumption of fruits/ Fellowship Director at the USF Eye glaucoma. J Glaucoma 2017;26;12;1161-68. vegetables with decreased risk of glaucoma among older 12. Davis BM, et al. Topical Coenzyme Q10 demonstrates African–American women in the study of osteoporotic fractures. Institute in Tampa. mitochondrial-mediated neuroprotection in a rodent model of Amer J Ophthal 2012;154:4:635-644. ocular hypertension. Mitochondrion 2017; 36: 114-123. 23. Kang, JH, et al. Association of dietary nitrate intake with 1. Age Related Eye Disease Study Group. A randomized, 13. LiuXQ, Chen MM, et al. Resveratrol Mitigates Rat Retinal primary open-angle glaucoma, a prospective analysis from the placebo-controlled, clinical trial of high-dose supplementation Ischemic Injury: The roles of matrix metalloproteinase-9, Nurses’ Health Study and Health Professionals Follow-up Study. with vitamins C and E, beta carotene, and zinc for age-related inducible nitric oxide, and heme oxygenase-1. Jour Oc Pharm JAMA Ophthalmology 2016;13:3:294-303. macular degeneration and vision loss: AREDS report no. 8. Arch Ther 2013;29:1:33-40. 24. Hepler RS, Frank IR. Marihuana smoking and intraocular Ophthalmol 2001;119:10:1417-1436. 14. Chung HS, Harris A, et al. Ginkgo biloba extract increases pressure. JAMA 1971;217:1392. 2. Asregadoo ER. Blood levels of thiamine and ascorbic acid in ocular blood fl ow velocity. J Ocul Pharmacol Ther 1999;15:3:233- 25. Green K. Marjuana smoking vs cannabinoids for glaucoma chronic open-angle glaucoma. Ann Ophthalmol 1979;11:1095– 40. therapy. Arch Ophthalmol 1998;116:1433-1437. 1100. 15. Quaranta LR, et al. Ginkgo biloba extract improves visual fi eld 26. Merritt JC, et al. Effect of marijuana on intraocular and blood 3. Virno M, Bucci MG, et al. Intravenous glycerol-vitamin C damage in some patients affected by normal-tension glaucoma. pressure in glaucoma. Ophthalmology 1980;87:3:222-8. (sodium salt) as osmotic agents to reduce intraocular pressure. Invest Ophth Vis Sci 2014;55:2417. 27. Porcella A, Maxia C, Gessa GL, Pani L. The synthetic Am J Ophthalmol 1966;62:824–833. 16. Gurses-Ozden R, Harris A, et al. Ginkgo biloba extract does cannabinoid WIN55212-2 decreases the intraocular pressure 4. Linner E. The pressure lowering effect of ascorbic acid in ocular not alter peripapillary retinal hemodynamics using Heidelberg in human glaucoma resistant to conventional therapies. Eur J hypertension. Acta Ophthalmol (Copenh) 1969;47:685–689. Retina Flowmetry in open-angle glaucoma. Invest Ophthalmol Vis Neurosci 2001;13:2:409-12. 5. Fishbein SL, Goodstein S. The pressure lowering effect of Sci 2002:42(Suppl) 28. Adelli GR, et. al. Development of a delta9-tetrahydrocannabinol ascorbic acid. Ann Ophthalmol 1972;4:487–491. 17. Guo X, et al. Author Response: Effect of Ginkgo biloba on amino acid-dicarboxylate prodrug with improved ocular 6. Wang SY, et al. Glaucoma Vitamins A, C, and E supplement visual fi eld and contrast sensitivity with NTG in Chinese patients: bioavailability. Inves Ophth Vis Sci 2017;58:4:2167-2179.

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REVIEW Rundown Edited by Arturo Chayet, MD

Some New Tricks With Gore-Tex Two ways to use the resilient suture material for fi xating intraocular lenses in challenging surgical cases. Walter Bethke, Editor in Chief

he Gore-Tex suture material is tion of the haptics. really matter what the white-to-white Tstrong, but doesn’t respond to ex- “One of the problems that we run diameter is, because the lasso technique ternal forces the way other sutures, into when performing intrascleral haptic gives you centimeters worth of haptic, such as vicryl or nylon, might. Because fi xation,” Dr. McKee explains, “is that, rather than just millimeters. To per- of these differences, and the comfort- with a glued IOL, sometimes there’s form the technique, you first go to a ing familiarity of other suture material, not enough haptic in patients with large spot near the tail of the Gore-Tex suture some surgeons are hesitant to employ eyes to really secure it to the sclera. The and poke a hole through the Gore-Tex Gore-Tex for maneuvers like fi xating next thought is, ‘Well, just use longer with a 30-ga. needle. You can then take an IOL in the setting of inadequate haptics,’ but that would mean develop- the needle itself, trailing the Gore-Tex, capsular support. In this article, a sur- ing a new IOL at the cost of millions of and pass it part of the way through the geon experienced in working with Go- dollars for just a limited distribution. In- hole you’ve made, but leave the suture re-Tex for specifi c surgical maneuvers dustry isn’t interested in doing that.” As on the metal of the needle. Then, take shares his tips and tricks. a solution, Dr. McKee makes, in effect, low-temperature loop cautery and hold a longer haptic with a Gore-Tex sutur- it near the suture hole where the nee- Intrascleral Haptic Fixation ing technique. He credits New York dle passes through it—but don’t touch surgeon Ken Rosenthal for being one of it. The heat melts the suture material Mesa, Arizona, ophthalmologist the fi rst, if not the fi rst, surgeon to use around the needle, creating a button- Yuri McKee, MD, says that Gore-Tex Gore-Tex in ocular surgery. hole in the very end of the suture, which has a lot of potential to assist surgeons “I use a lasso technique to make a ‘lon- reinforces it. This is similar to the way a with diffi cult cases such as those re- ger’ haptic,” Dr. McKee explains. “The shirtmaker takes extra thread and sews quiring some sort of intrascleral fi xa- technique is useful because it doesn’t it around the buttonhole of a shirt; the

A B C D

Figure 1. (A) To create a Gore-Tex lasso, fi rst punch a hole near the tail of the suture, then (B) pass the needle through the hole and (C) expose the hole to cautery to reinforce it. (D) Creating a bulb at the end of a haptic with cautery.

February 2018 | reviewofophthalmology.com | 47

047_rp0218_rcr.indd 47 1/26/18 3:02 PM Refractive/Cataract

REVIEW Rundown

A B C D

Figure 2. (A) Looping the lasso from Fig. 1 around the haptic then pulling it tight (B). The bulb at the end of the haptic helps keep it in place. A surgical shot of an externalized haptic with Gore-Tex being run through a strut (C) and the haptic is then sutured down (D).

extra reinforcement around the hole and the suture.” source for an infection; and you have to prevents the hole from propagating in With this in mind, Dr. McKee pulls rotate a big knot through a small hole, different directions. This step is critical, the other haptic through the other which can be the source for a leak. It’s because if you were to just take the su- scleral tunnel, exposes the tip to the also hard to do and the suture might ture and poke it through its own tail and cautery, and ties the lasso around it. break.” then pull on it, it tears out instantly with “I then pass the Gore-Tex in an intra- As an alternative, Dr. McKee makes hardly any force being applied. But, scleral pass in the same direction and a modification to the Gore-Tex su- when you make that little hole in the tail plane that the haptic would have trav- ture that allows surgeons to get a tight of the suture and then heat seal it, you eled in, and then double the Gore-Tex closure without a knot. “I make four have a very strong lasso.” backward along that same path parallel or fi ve holes in a line along the tail of To sclerally fi xate an IOL, Dr. McK- to it,” he says. “That basically makes a the Gore-Tex, separated by 0.5 mm,” ee fi rst implants the IOL, then creates haptic that would be two or three times he explains. “I then bring the cautery scleral tunnels directly opposite each longer than it would have been nor- near the holes—but not touching—to other. Through one tunnel, he pulls one mally. Then, where it exits the sclera, I strengthen them. That’s one end of the of the IOL haptics and snares it with the just heat-seal the tip or cut the suture, suture. I pass this through the sclera, Gore-Tex suture. He then sutures down and it just fl attens out to a mushroom around the loop or strut of the IOL, the haptic. Through the other scleral there, making for a stable closure and and then bring it back out of the sclera. tunnel, he uses a different technique. extension of the haptic.” Then, rather than tie it, I pass the nee- “With the lasso created, you have a lot dle through some sclera, then through of options,” Dr. McKee continues. “You Forget the Knot one of the holes in the suture, then back can lasso an eyelet, around a haptic or through the sclera, et cetera, zigzagging through an IOL strut. I take the three- Dr. McKee says that, when dealing it back and forth like a sewing machine, piece IOL and apply the heat loop cau- with IOLs with a strut or loop such as incorporating some sclera and suture tery near the end of the haptic, which the B+L enVista or Akreos, some sur- with each bite. The tension created by creates a small bulb on the end. I then geons pass the Gore-Tex through the looping your suture through four or fi ve take the Gore-Tex lasso and tighten it strut/loop and then push it through the holes and then running it back through around the haptic and pull until it until sclera, tie it on top of the sclera and then the sclera is actually stronger than a it eventually stops at the little bulb I rotate it back into the eye. This isn’t ide- knot. The harder you pull it, the tighter created with the cautery. This results in al in his opinion. “For me, rotating the it gets.” a surface in which there’s basically no knot back into the eye is a problem,” he bulk in the knot, the lasso or the con- says, “because you have a full-thickness Dr. McKee has no fi nancial interest in nection you made between the haptic pass through the sclera, which can be a any of the products mentioned.

A B C D

Figure 3. (A, cont’d from Fig. 2) The other externalized haptic is captured with the Gore-Tex lasso and then sutured in place (B). in a second technique, multiple holes are made in the suture (C). The needle is passed through the holes and sclera, making a tight closure.

48 | Review of Ophthalmology | February 2018

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REVIEW Edited by Carl Regillo, MD, and Emmett T. Cunningham Jr., MD, PhD, MPH

Posterior Scleritis: A Diagnostic Challenge A detailed look at the signs and symptoms to watch for, and how to follow up diagnosis with the appropriate therapy.

Lana M. Rifkin, MD Boston

osterior scleritis is a rare but poten- Table 1. Diagnostic Tests Ptially vision-threatening condition that’s often underdiagnosed due to its Test Associated Disease perplexing and varied clinical presen- PPD or Tuberculosis tation. It’s a painful inflammation of quantiFERON Gold the sclera posterior to the ora serrata RPR Syphilis which can be seen in all age groups and FTA-Abs all ethnicities, although it more com- Rheumatoid Factor Rheumatoid arthritis monly occurs in middle-aged women.1 Anti-CCP Posterior scleritis represents approxi- ANA Sytemic lupus erythematous mately 10 percent of all cases of scleri- ACE Sarcoidosis tis, half of which can be associated with Lysozyme systemic disease—most commonly Chest X-ray rheumatoid arthritis—but sometimes ANCA Granulomatous polyangiitis; Polyarteritis nodose with more rare but life-threatening conditions such as systemic lupus ery- HLA-B27 Ankylosing spondylitis; Psoriasis thematous and granulomatous poly- angiitis. A thorough review of systems is crucial in the evaluation of these of posterior scleritis is moderate to causing angle closure without pupil- patients, with a particular focus on severe pain. Patients will often de- lary block, blockage of the outflow systemic signs of rheumatoid arthritis scribe a deep, dull, boring pain that, track due to infl ammation, elevated such as joint pain, sinus issues or epi- classically, wakes them from sleep. episcleral venous pressure, peripheral staxis that may be associated with GPA, There may be associated pain with ex- anterior synechiae or neovasculariza- breathing trouble that may lead one traocular motility, proptosis or other tion. towards a diagnosis of sarcoidosis, and orbital signs. The degree of effect on Deep redness and tenderness to skin disorders that may lead towards a vision can be variable, from minimally palpation due to anterior scleritis also diagnosis of psoriasis or lupus. affected to signifi cant vision loss. In- may or may not be present in cases of traocular pressure may be elevated posterior scleritis. On physical exami- Clinical Presentation in up to half of patients with scleritis, nation, it’s important to lift the eye- which may be due to rotation of the lids and ask the patient to look in all The hallmark presenting symptom ciliary body and iris root into the angle directions of gaze, as subtle anterior

50 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

050_rp0218_retinal.indd 50 1/26/18 4:00 PM scleritis may not be immediately evi- well as a CBC and CMP and chest associated with posterior scleritis, dent. Patients with strictly posterior X-ray should be obtained. such as optic nerve edema or serous scleritis may not have ocular redness retinal detachment, can also be dem- but will describe discomfort with mo- Imaging in Posterior Scleritis onstrated on FA. ICG can demon- tility and may show restriction of eye strate fl uorescent pinpoints in active movement. Various imaging methods can yield infl ammation.2 Slit lamp biomicroscopy may dem- important information in suspected • Orbital CT scan. CT can help onstrate corneal edema, shallowing cases of posterior scleritis. identify posterior infl ammation, dem- of the anterior chamber with anterior • B-scan ultrasonography. This onstrating increased choroidal thick- bowing of the iris and mild to moder- can be crucial to the diagnosis of pos- ness. In general, ultrasonography is ate anterior chamber cell. terior scleritis, with the pathogno- considered superior to CT in imaging Fundus examination may show monic T-sign due to fl uid collecting for posterior scleritis, but the latter swelling of the optic nerve, exuda- in the posterior episcleral space and can be helpful in ruling out idiopathic tive retinal detachment or choroidal extending around the optic nerve. orbital infl ammation and myositis. effusions. • Optical coherence tomogra- phy. OCT, particularly with enhanced Treatment Workup depth imaging, can be quite helpful in the diagnosis of posterior scleritis, The treatment of posterior scleri- All patients presenting with scleritis demonstrating increased thickness of tis can be quite challenging. Topical should be worked up for associated the choroid. Often, subretinal fluid NSAIDs and topical corticosteroids systemic disease. First and foremost, can be noted, even presenting in mul- aren’t typically helpful, so systemic it’s imperative to rule out infection tiple foci. therapy is often initiated. Oral non- with tuberculin skin testing or serum • Fluorescein and indocyanine steroidals can be effective with various interferon gamma release assays such green angiography. While posterior appropriate regimens, such as ibupro- as quantiFERON Gold, as well as scleritis doesn’t have characteristic fen 600 to 800 mg q.i.d., piroxicam 20 RPR and FTA-Abs testing for syphilis. signs on FA, this modality can also mg daily and naprosyn 375 mg b.i.d., Rheumatoid factor and anti-citrulli- be helpful in distinguishing posterior to name a few. In cases unresponsive nated protein antibodies, ANA, ACE scleritis from other, similarly present- to oral NSAIDs, high-dose systemic (if the patient is not on an ACE inhibi- ing issues, such as central serous reti- corticosteroids are often used, with tor), lysozyme, ANCA, HLA-B27, as nopathy. Other characteristics often typical doses of 1 mg/kg/day or approx-

Figure 1. Fluorescein angiography demonstrating hypofl uorescent Figure 2. Indocyanine green angiography showing hypercyanescent spots outside the arcades, bilaterally. spots outside the arcades, bilaterally.

Figure 3. OCT with extended-depth imaging of right and left eye showing increased choroidal thickness bilaterally, as well as mild retinal folds.

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050_rp0218_retinal.indd 51 1/26/18 4:00 PM Retinal

REVIEW Insider

imately 60 mg of prednisone The patient was started on daily. These are tapered slowly IOP-lowering drops and cyclo- over several weeks, with care- plegics, as well as 60 mg of oral ful consideration of potential prednisone. One week later, side effects such as weight gain, IOP returned to normal, vision mood instability, blood-sugar improved, and OCT showed abnormalities, etc. clear improvement, in choroidal If the patient continues to thickness. The patient’s system- demonstrate active disease or ic corticosteroids are currently is unable to tolerate corticoste- being tapered. roids, prompt corticosteroid- sparing immunosuppression Case Example 2 is often warranted. Anti-me- tabolites such as methotrexate A 43-year-old Caucasian man and mycophenolate mofetil presented to an outside oph- are employed, often to their thalmologist with a complaint maximal doses of 25 mg/week of a red right eye. He was ini- of methotrexate or 1,500 mg tially diagnosed with episcleritis b.i.d. of mycophenolate. These and started on topical steroids. medications may take up to He then developed pain wak- six months for full effect and ing him from sleep, along with some patients may require a proptosis and restriction in eye Figure 4. CT scan (axial view) showing increased choroidal faster-acting solution. In these thickness of the right eye, with a normal left eye. movement. An orbital process cases, biologics such as TNF was suspected and CT was or- inhibitors (e.g., adalimumab, dered, demonstrating increased infl iximab) may be necessary. choroidal thickening of the right Rituximab has demonstrated eye (Figure 4). He was referred good effi cacy in the treatment to the uveitis service, where B- of scleritis, particularly in cases scan was performed (Figure 5) associated with systemic dis- and he was diagnosed with an- ease. Scleritis associated with terior and posterior scleritis and GPA may require the use of started on oral prednisone. He cyclophosphamide. These pa- was tapered over several weeks tients are typically co-managed but fl ared, and thus required ste- with rheumatologists, with roid-sparing systemic immuno- guidance from the ophthal- suppression with methotrexate. mologist regarding treatment The patient’s infl ammation has dosing and response. resolved and he’s quiet and pain Prompt recognition and Figure 5. B-scan ultrasound demonstrating thickened free. appropriate, often aggressive, choroid with fl uid in sub-Tenon’s space. treatment is key to recovery and Dr. Rifkin is a uveitis specialist who preservation of vision. angles bilaterally with 360 degrees of practices at Ophthalmic Consultants iridocorneal touch. Fundus examina- of Boston. She’s also director of the Case Example 1 tion was notable for bilateral choroi- Uveitis Service at New England Eye dal effusions. Fluorescein angiography Center, and is an assistant professor A 27-year-old Caucasian woman pre- (Figure 1) demonstrated hypofl uores- of ophthalmology at Tufts School of sented with bilaterally decreased vision cent spots outside the arcades with Medicine. She can be reached at lana. and pain. Her visual acuity was 20/200 no evidence of leakage. Indocyanine [email protected]. bilaterally, with a signficant myopic green (Figure 2) showed hypercyanes- 1. Lavric A, Gonzalez-Lopez JJ, Majumber PD, et al. Posterior shift. Intraocular pressure was mea- cent spots in the same areas. Both eyes Scleritis: Analysis of Epidemiology, Clinical Factors, and Risk of Recurrence in a Cohort of 114 Patients. Ocul Immunol Infl amm sured to be 55 mmHg in both eyes and showed diffusely thickened choroid on 2016;24:1: 6-15. slit lamp examination revealed shallow OCT (Figure 3). 2. Auer, Herborn, Indocyanine green angiographic features in posterior scleritis. Am J Ophthlmol. 1998;126:3:471-6

52 | Review of Ophthalmology | February 2018

050_rp0218_retinal.indd 52 1/26/18 4:00 PM The Rick Bay Foundation for Excellence in Eyecare Education www.rickbayfoundation.org Support the Education of Future Healthcare & Eyecare Professionals

About Rick Scholarships are awarded to advance the education Rick Bay served as the publisher of students in both Optometry and Ophthalmology, of The Review Group for more than 20 years. and are chosen by their school based on qualities that embody Rick’s commitment to the profession, including To those who worked for him, he was integrity, compassion, partnership and dedication to the a leader whose essence was based greater good. in a fi erce and boundless loyalty. Interested in being a partner with us?

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2015_rickbay_housead.indd 1 7/5/17 3:00 PM Research Review REVIEW

Surgical Outcomes Of GATT in POAG

n a retrospective chart review, re- one week and one month postopera- (J0178, J2778, J9035, J3490 and J3590). Isearchers from Wills Eye Hospital’s tively was 38 percent and 6 percent, Researchers identifi ed claims using the glaucoma research center, Sidney respectively. Overall GATT success Medicare provider utilization and pay- Kimmel Medical College and the De- rates among white and black patients ment data from the Centers for Medi- partment of Biostatistics at Thomas were 69 percent and 42 percent, re- care and Medicaid Services among Jefferson University evaluated the ef- spectively, which was statistically sig- fee-for-service Medicare benefi ciaries ficacy and safety of gonioscopy-as- nifi cant (p<0.05). from 2012 to 2015; 2008 claims were sisted transluminal trabeculotomy in The future of GATT as a minimally- acquired from the 100-percent FFS patients with open-angle glaucoma. invasive glaucoma surgery in adults Part B Medicare claims fi le. Research- In this study, researchers conducted seems promising, these researchers ers determined OCT research costs by a chart review of adult patients who claim. This position is supported by searching for grants awarded by the underwent GATT due to inadequate- GATT’s low rate of long-term compli- NIH and NSF from inception to 2015. ly controlled intraocular pressure or cations and the conjunctiva-sparing They discounted all costs and savings poor tolerance to medication. Main nature of the surgery. by 3 percent annually and adjusted for outcome measures were success rate, J Glaucoma 2017 Dec;16:1137-1143 infl ation to 2015 dollars. IOP and number of glaucoma medi- Rahmatnejad K, Pruzan NL, Amanullah S, et al. The researchers determined that cations. Success was defined as IOP between 2008 and 2015, the U.S. gov- reduction >20 percent from baseline Savings From Research ernment accrued an estimated savings or IOP between 5 and 21 mm Hg, and Researchers compared patient and of $9 billion, while nvAMD patients no need for further glaucoma surgery. Medicare savings from the use of opti- saw an estimated savings of $2.2 bil- When success criteria were not met cal coherence tomography in guiding lion, from the use of OCT to guide for any postoperative visit longer than therapy for neovascular age-related personalized anti-VEGF treatment. three months after surgery, failure was macular degeneration, with funding The $9 billion represents a 21-fold re- determined. from the National Institutes of Health turn on government investment into In total, 66 patients, average age and the National Science Founda- developing the technology through 62.9 ±14.9 years (50.8-percent fe- tion in developing OCT, as part of an NIH and NSF grants, they added. male) were included in the analysis. observational cohort study. (Several The researchers added that, al- Average follow-up was 11.9 months of the study’s authors have a fi nancial though an overall cost-benefit ratio (range: three to 30 months) and over- interest in OCT devices and/or com- of government-sponsored research is all success rate was 63 percent. Mean panies.) diffi cult to estimate because the ben- IOP was 26.1 ±9.9 mmHg preop- The main outcome measures were efi t may be diffuse and delayed, their eratively and 14.6 ±4.7 mmHg at 12 spending by Medicare, as tracked fi ndings reveal that the investment in months (a 44-percent IOP decrease; by Current Procedural Terminol- OCT over two decades was recouped p<0.001). Mean number of medica- ogy codes for intravitreal injections many times over within a few years tions decreased from 3.1 ±1.1 pre- (67028), retinal OCT imaging (92134) through better personalized therapy. operatively to 1.2 ±0.9 at 12 months and anti-vascular endothelial growth Am J Ophthalmol 2017;185:115 (p<0.001). The rate of hyphema at factor treatment–specific J-codes Windsor MA, Sun SJJ, Frick KD, et al.

54 | Review of Ophthalmology | February 2018 This article has no commercial sponsorship.

0054_rp0218_rr.indd54_rp0218_rr.indd 5454 11/26/18/26/18 1:571:57 PMPM Pediatric Patient Edited by Wendy Huang, MD REVIEW

Pearls In Pediatric Ocular Oncology A brief review of diagnosis and treatment for these life-threatening disorders. Raafay Sophie, MD, and Aparna Ramasubramanian, MD Louisville, Ky.

hough pediatric eye tumors are rare, Tit’s vital to diagnose them in a timely fashion in order to save the eye and, in many cases, the patient’s life. This article reviews key highlights for the common spectrum of ocular tumors in the pediatric population.

Retinoblastoma Figure 1. (A) Nasal retinoblastoma with overlying vitreous seeds treated with three cycles Retinoblastoma is the most common of intraarterial melphalan, showing good tumor response and calcifi ed vitreous seeds (B). primary intraocular tumor in children, with an incidence of 11.8 per million to developing a pineoblastoma and 1) (Figure 2A&B). in the United States.1 It’s caused by have a higher risk of developing sec- • Treatment. Patients with uni- mutations in the tumor suppressor ondary tumors. Following is a de- lateral disease may undergo focally RB1 gene (located on Chromosome scription of diagnosis, treatment and destructive therapy (cryopexy, laser 13q14); both alleles must be affected screening considerations. photocoagulation, hyperthermia and for tumorigenesis. These mutations • Clinical diagnosis. The most plaque irradiation) in conjunction can occur sporadically, if so, typically common presenting sign of retinoblas- with systemic chemoreduction. Re- presenting with unilateral disease at toma is leukocoria followed by stra- cently, intra-arterial chemotherapy is around 24 months. However, in 40 bismus. On exam the tumor appears being employed for treatment (Fig- percent of patients, retinoblastoma in- as a translucent or white mass, and ure 1), while enucleation is reserved volves an autosomal-dominant inher- may be endophytic (into the vitreous for large tumors or recalcitrant cases. ited heterozygous germline mutation cavity), exophytic (towards the sub- Bilateral cases will require systemic followed by a subsequent mutation retinal space), or diffusely infi ltrating. chemotherapy.2 on the second allele. This heritable Ultrasound will show calcifi cation in 90 • Family screening and genetic form (approximately 10 percent have percent of cases, while CT-scan should counseling. In patients with bilateral a positive family history) classically be avoided in suspected cases. The dif- retinoblastoma there is a 50-percent presents earlier, at around 12 months ferential diagnosis for retinoblastoma chance of the offspring being affected. with bilateral (or multiple unilateral) includes persistent fetal vasculature, If these patients have an identified disease, and patients are more prone toxocariasis and Coats’ disease (Table germline mutation, DNA testing can

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REVIEW Patient

Table 1: Differentiating Features Between Retinoblastoma and Coats’ Disease*

Retinoblastoma Coats’ Disease Features Family History 10 percent of patients Sporadic Mean Age of 1.5 years 5 years Onset Gender Male=female Mostly affects males Laterality Unilateral or bilateral Unilateral Genetics Mutation in RB1 on ± Somatic mutation on chromosome 13q14 NDP gene on chromosome Xp11.4 Ocular Exam Vitreous White fl uffy seeds Normal Intraocular Mass White/translucent mass No mass, may present as subretinal gliotic nodule Figure 2. (A) Retinoblastoma with total retinal detachment showing Retinal Vessels Dilated feeding artery Irregular dilation of retinal the dilated tortuous vessels that dip in to feed the tumor. (B) Coats’ and tortuous draining vessels, telengiectasia disease with total retinal detachment showing the telangiectatic vein vessels in the periphery. (C) Fleshy tumor arising from the ciliary Retinal Absent Present body in a child suggestive of medulloepithelioma. (D) Iris stromal Exudation cyst in a child. Retinal Exudative with fl uffy Exudative with yellow- Detachment white subretinal seeds white cholesterol crystals Imaging In either case, DNA testing can be pursued in pregnancy Ultrasound Solid retinal mass with Retinal detachment; or in neonates to establish risk. If patients with unilateral intratumoral Linear calcifi cation at level retinoblastoma have no germline mutation and no tumor calcifi cations (high- of RPE in rare cases is available for testing, the risk to the offspring is less than 5 intensity echoes); percent, no testing is possible and the child must undergo Retinal detachment surveillance eye exams. Computed Hyperattenuated Retinal detachment with Tomography intraocular mass with hyperattenuating subretinal The recommended screening for familial retinoblastoma calcifi cation exudates; no calcifi cation is for an initial exam within two weeks of birth, monthly Magnetic T1- isotense or slightly T1- and T2-hyperintense to exams up to age 3 months, bi-monthly exams till age 1, Resonance hyperintense to vitreous due to exudates tri-monthly exams till age 2, an exam every four months till Imaging vitreous; age 3 and then semi-annual exams until age 4.3 Using this T2-hypointense to vitreous protocol, nearly 100 percent of familial tumors are detected Fluorescein Early arterial fi lling Early arterial and venous by 12 months. Angiography within tumor with phase demonstrate areas If a germline mutation is identifi ed in a child and the leakage on venous of nonperfusion and parents tested negative, it’s possible that one parent could phase. Late phase arterial and venular have germline mosaicism, in which case testing of siblings is demonstrates intense, telangiectasia with light recommended. If mosaicism for germline mutation is iden- well-circumscribed bulbs. Late phase shows hyperfl uorescence of leakage of dye tifi ed in the child, the mutation was a post-zygotic event and tumor no testing of siblings is warranted.2

*adapted from Ramasubramanian A, Shields CL. Retinoblastoma. First ed: Jaypee Brothers Medical Publisher (P) Ltd.; 2012 Medulloepithelioma (Diktyoma)

be performed in pregnancy or in neonates to establish the This is a rare embryonic tumor of the non-pigmented risk to the offspring. If testing of the patient fails to identify ciliary epithelium. It’s the second most common pediatric a germline mutation, the child must undergo surveillance primary intraocular tumor. The diffi cult direct visualization eye exams. of these tumors may lead to late diagnosis, misdiagnosis In patients with unilateral retinoblastoma, a germline and improper initial management. Even after symptoms mutation may occur in 10 to 15 percent of patients, the develop, the possibility of a tumor is often overlooked, as risk to an offspring is similarly 50 percent. In the remaining patients are treated for secondary complications of the patients, if tumor cells test positive for a somatic mutation, tumor such as cataract or glaucoma. Later, as the tumor there is less than a 5-percent risk for the affected offspring. slowly grows, it may be seen in the pupil, distort the iris, or

56 | Review of Ophthalmology | February 2018

055_rp0218_peds.indd 56 1/26/18 3:51 PM invade adjacent tissues. The tumor ap- material. These cysts may break and ary body mass with intratumoral cys- pears as an irregularly shaped, smooth, fl oat off into the aqueous or vitreous tic spaces.4 A characteristic retrolental fl eshy pink lesion arising from the cili- humor. Ultrasound biomicroscopy and neoplastic cyclitic membrane may be ary body (Figure 2C), oftenwith large AS-OCT are useful for visualization of found in half of the cases.5 Histologi- cystic spaces that contain vitreous-like the medium-to-highly reflective cili- cally it’s classified as non-teratoid or

Table 2. Phakomatoses and Their Diagnostic Features

Disorder Diagnostic Criteria Ocular Features Neurofi bromatosis-I (Von Recklinghausen disease) • six or more cafe-au-lait spots (Figure 3A); • Eyelid: Neurofi broma (Figure 3B), Autosomal dominant, (Chromosome 17) • two or more neurofi bromas of any type, or one cafe au lait Prevalence: 1:4,000 or more plexiform neurofi broma; • Conjunctiva: Plexiform neurofi broma • freckling in the axilla or groin; • Cornea: Prominent corneal nerves • optic glioma; • Iris: Iris ectropion (Figure 3D), • two or more Lisch nodules; nevus, Lisch nodules • a distinctive bony lesion: dysplasia of the • Glaucoma: Ipsilateral to the sphenoid bone or dysplasia or thinning of long plexiform neurofi broma bone cortex; and/or • Retina/Choroid: Retinal glial • a fi rst-degree relative with NF I hamartoma, choroidal thickening • Orbit: Optic nerve glioma (Figure 3C), Pulsating exophthalmos (absence of sphenoid wing), neurofi broma, schwannoma

Neurofi bromatosis-II • detection of bilateral acoustic neuroma by • Lens: Cortical cataract, posterior Autosomal dominant (Chromosome 22) imaging procedures; subcapsular cataract Prevalence: 1:40,000 • fi rst-degree relative with NF II and the • Retina: Combined hamartoma, occurrence of neurofi broma, meningiomas, Epiretinal membrane glioma, or schwannoma; • Orbit: Optic nerve sheath • fi rst-degree relative with NF II and the occur- meningioma, optic nerve glioma rence of juvenile posterior subcapsular cataract

Tuberous Sclerosis (Bourneville Syndrome) Mental retardation, seizures and facial • calcifi ed or non-calcifi ed Autosomal dominant, 60 percent are sporadic angiofi broma hamartoma (Figure 4A), seen in 40 to mutations CNS features: 50 percent of TS patients; TSC1 (Chromosome 9): familial • subependymal astrocytic hamartomas; and • early-onset cataracts; TSC2 (Chromosome 16): sporadic, more aggressive • cortical astrocytic hamartomas. • hamartomas of the iris pigment Prevalence: 1:6,000 Systemic features: epithelium and ciliary body • renal angiomyolipoma; epithelium; • cardiac rhabdomyoma; • eyelid angiofi bromas; • pleural cysts; and/or • strabismus; • occasional similar hamartomas of liver, • colobomas; and/or thyroid, pancreas, testes, etc. • iris depigmentation

Sturge-Weber Syndrome (Encephalofacial CNS Features: • facial hemangioma; Angiomatosis) • leptomeningeal angiomatosis; • diffuse choroidal hemangioma Not genetically transmitted • cerebral calcifi cation (rail road track sign); (Figure 4B); Prevalence: 1:50,000 • mental retardation; and/or • glaucoma • convulsions

Von Hippel Lindau Syndrome (Retinal Angiomatosis) CNS features: • screening usually starts at age 5; Autosomal dominant (Chromosome 3) • cerebellar hemangioblastoma; and/or • retinal capillary hemangioma Prevalence: 1:50,000 • syringomyelia. (Figure 4C); Systemic features: • usually multiple tumors, peripheral • pheochromocytoma; more common; • renal cysts; • treatment consists of laser, • hypernephroma; cryotherapy or PDT • pancreatic cysts; and/or • epididymal cysts (Continued on next page)

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REVIEW Patient

Table 2. Phakomatoses and Their Diagnostic Features (continued from p. 57)

Disorder Diagnostic Criteria Ocular Features Ataxia Telengiectasia (Louis-Bar Syndrome) CNS features: • bilateral bulbar conjunctival telangiectasias Autosomal recessive (Chromosome 11) • cerebellar ataxia that develop between 3 and 5 years of age; Prevalence: 1:30,000 Systemic features: and/or • skin telangiectasias; • ocular motor apraxia • immune defi ciency, thymic hypoplasis; and/or • a tendency to develop malignancies such as lymphoma and leukemia

Wyburn-Mason Syndrome (Retinal Racemose CNS/Systemic/Ocular features: • arterio-venous malformation of the retina; Angioma) • ipsilateral vascular malformation of brain, fl uorescein angiogram shows no leakage Not genetically transmitted orbit and mandible Prevalence: fewer than 100 reported cases Unilateral

Incontinentia Pigmenti (Bloch-Sulzberger CNS features: • proliferative retinal vasculopathy similar to Syndrome) • seizures; retinopathy of prematurity X-linked dominant (“NEMO” gene) • developmental delay; and/or Prevalence: 1:390,000 • mental retardation. Systemic features: • skin abnormalities (“Splashed-paint” appearance); • alopecia; and/or • dental abnormalities

teratoid (it often has hyaline cartilage), been used, including aspiration, cryo- suspicion. Optical coherence tomog- and as benign or malignant. Unlike therapy, laser and surgical removal.7,8 raphy and newer imaging modalities medulloepithelioma of the central ner- Recently, physicians have had con- are currently being investigated for vous system, metastasis is rare. Treat- siderable success treating these cases detection purposes. Once a glioma is ment options include cryotherapy, lo- with sclerosing therapy using absolute detected, it’s monitored with regular cal resection, plaque radiotherapy and alcohol.9 ophthalmic exams and MRI, with the external beam radiotherapy but, often, frequency depending on the institu- enucleation is required. Phakomatoses tion’s protocol.

Iris Stromal Cysts Tumors often occur in combination Capillary Hemangioma with neurocutaneous disorders or pha- In children, these are often primary komatoses. Some salient features of These hamartomatous growths cysts; acquired cysts mostly occur in common phakomatoses are outlined composed of proliferating capillary adults.6 In contrast to iris pigment epi- in Table 2. endothelial cells are the most com- thelium cysts, these tend to enlarge In cases of optic nerve glioma (as can mon benign tumors of infancy. They aggressively, especially in children. occur with neurofibromatosis, seen occur in 1 to 3 percent of term new- Iris stromal cysts appear as a translu- in Table 2), there are some screen- borns, are more common in prema- cent mass occupying the anterior iris, ing guidelines to note: Although there ture infants and occur in varying fre- expanding to fi ll much of the anterior is some non-uniformity regarding quency across races (10 to 12 percent chamber and covering the pupil, lead- screening frequency and duration in in white, non-Hispanic infants; 1.4 ing to angle occlusion and glaucoma the literature, in most centers screen- percent in black infants and 0.8 per- (Figure 2D). Occasionally, the cyst ing is performed every six months until cent in Asian infants). The salient fea- can rupture, causing anterior uveitis, age 6 and then annually up to ages tures are the following: secondary glaucoma and an increased 16 to 18.10 This includes visual acu- • Clinical presentation. Most risk for epithelial downgrowth. These ity testing, pupillary refl ex testing and hemangiomas are clinically insignif- cysts are often diffi cult to manage and fundoscopy, while a brain MRI is usu- icant at birth. They present as ery- a variety of treatment strategies have ally reserved for when there is clinical thematous macules or telangiectasia

58 | Review of Ophthalmology | February 2018

0055_rp0218_peds.indd55_rp0218_peds.indd 5588 11/26/18/26/18 3:523:52 PMPM (Figure 4D). The natural 9 months of age. The child is history is of rapid prolif- then weaned off of this over eration in the fi rst several two to three weeks (similar months of life, typically to initiation) and the heman- followed by regression af- gioma observed for any signs ter a year. Rarely, they may of recurrence. If there is any ulcerate or bleed. A large, recurrence, propranalol is re- facial, plaque-like capillary started. hemangioma involving one Pulsed dye laser may be or more dermatomes may used to treat residual telan- be associated with an X- giectasias, and residual tex- linked dominant systemic ture irregularities can be im- condition called PHACES Figure 3. Features of neurofi bromatosis-1 include café-au-lait spots proved by resurfacing with Syndrome (posterior fossa (A), upper eyelid plexiform neurofi broma (B), optic nerve glioma (C) carbon dioxide or erbium la- brain malformation, facial and congenital iris ectropion (D). sers. Topical timolol may be hemangiomas (segmental, used for superficial heman- >5 cm), arterial anomalies, cardiac (b.i.d.) for the fi rst week. This is esca- giomas. Steroids are rarely used due anomalies and aortic coarctation, eye lated to 2.1 mg/kg/day (b.i.d.) in the to the side effects and the effi cacy of abnormalities, sternal cleft and supra- second week and treatment response propranolol. Interferon alpha-2a and/ umbilical raphe syndrome). is assessed. If the treatment is suc- or vincristine may be used in severe • Treatment. Indications for in- cessful, this dose is continued, or the cases, and surgery may be required tervention include occlusion of the dose may be escalated to 3.4 mg/kg/ either as a primary or reconstructive visual axis, induction of astigmatism, day (b.i.d.) and continued. At the start procedure. corneal exposure due to severe pro- of each dose increment, heart rate and ptosis and optic nerve compression blood pressure should be monitored Dr. Sophie is a resident physician by a rapidly growing tumor. A deep for two hours. and Dr. Ramasubramanian is an as- hematoma causing proptosis mer- Side effects of this treatment in- sistant professor at the University of its imaging to assess the tumor size. clude bradycardia, hypotension, Louisville’s Department of Ophthal- Non-ocular indications include hy- hypoglycemia and gastrointestinal mology. They have no fi nancial inter- pertrophy of epidermal and subcu- disturbances. Propranalol should est in any products mentioned here. taneous tissue leading to macera- be administered along with feeding tion, erosion of epidermis; or even and should be withheld if a child is This work was supported in part cardiac, hematologic and pulmonary not eating or is vomiting. Therapy is by an unrestricted institutional grant complications, as in the case of a size- continued until the complete regres- from Research to Prevent Blindness, able hematoma. Therapies include sion of hemangioma occurs or until New York, N.Y. beta-blockers (topical or 1. Broaddus E, Topham A, Singh AD. Incidence systemic), steroids (intrale- of retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 2009;93:21-3. sional or systemic), surgery, 2. Ramasubramanian A, Shields CL. Retino- laser and radiation. blastoma. First ed. Jaypee Brothers Medical Publisher Ltd.; 2012. We prefer using systemic 3. Moll AC, Imhof SM, Meeteren AY, Boers M. At what age could screening for familial retinoblastoma be propranolol as follows: After stopped? A register-based study 1945-98. Br J Ophthalmol 2000;84:1170-2. performing a complete ocu- 4. Gunduz K, Hosal BM, Zilelioglu G, Gunalp I. The lar exam and ruling out the use of ultrasound biomicroscopy in the evaluation of anterior segment tumors and simulating possibility of PHACES, the conditions. Ophthalmologica 2007;221:305-12. 5. Kaliki S, Shields CL, Eagle RC, Jr., et al. Ciliary patient is sent to a pediatri- body medulloepithelioma: Analysis of 41 cases. cian where heart rate, blood Ophthalmology 2013;120:2552-9. 6. Shields CL, Kancherla S, Patel J, et al. Clinical pressure, blood sugars and an survey of 3680 iris tumors based on patient age at presentation. Ophthalmology 2012;119:407-14. ECG are performed. If the 7. Shields JA, Shields CL, Lois N, Mercado G. Iris cysts in children: Classifi cation, incidence, and ECG is abnormal, then car- management. The 1998 Torrence A Makley Jr diology consultation, echo- Lecture. Br J Ophthalmol 1999;83:334-8. 8. Lois N, Shields CL, Shields JA, Mercado G, De cardiogram and inpatient Potter P. Primary iris stromal cysts. A report of 17 cases. Ophthalmology 1998;105:1317-22. treatment may be required. Figure 4. Astrocytic hamartoma in a patient with tuberous sclero- 9. Shields CL, Arepalli S, Lally EB, Lally SE, Shields If the pediatrician clears the JA. Iris stromal cyst management with absolute sis (A). Diffuse choroidal hemangioma in a patient with Sturge- alcohol-induced sclerosis in 16 patients. JAMA patient, we start outpatient Weber syndrome, note the dark pigment, optic nerve cupping and Ophthalmol 2014;132:703-8. 10. Caen S, Cassiman C, Legius E, et al. Comparative treatment with propranolol peripheral vessel shunting (B). Retinal capillary hemangioma in study of the ophthalmological examinations in Von Hippel-Lindau disease (C) and capillary hemangioma (D). neurofi bromatosis type 1. Eur J Paediatr Neurol at a dose of 1.2 mg/kg/day 2015;19:415-22.

February 2018 | reviewofophthalmology.com | 59

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62 | Review of Ophthalmology | February 2018

ROPH0218.indd 62 1/29/18 5:17 AM 063_rp0218_wills.indd 63 What isyourdiagnosis? furtherworkupwouldyoupursue?Thediagnosis appearsonp. 64. telangiectasia. telangiectasia. inferiorly. Therewassubtletemporalretinal extended totheoraserratatemporallyand ent andintermixedwithsubretinalfl intraretinal macularexudationwasconflu- diameter and asuperiorlylocatedretinalcyst10mmin prominent macularexudationinthelefteye oncology consultation. mass OS.Thechildwasreferredforanocular mal fi ndings OD, andayellow-whitemacular In-office fundusexaminationrevealednor- pupillary reflex)wasnotedinthelefteye. afferent pupillarydefect.Xanthocoria(yellow round andreactivebilaterallywithoutrelative ing, anditwasfi x andfollowOS.Pupilswere ed visualacuitywas20/40ODbyAllentest- Examination grandfather, cervicalcancerinhismaternalgrandmother, andcoloncancerinhismaternalgreatgrandmother. tent. Pasteyeandmedicalhistorywereotherwiseunremarkable.Familywaspositiveforlivercancerinhispaternal natal intensivecareunitadmissionfor23dayssecondarytolungprematurity, andtheinfantwasmonitoredinanoxygen Medical History and thechildwasotherwisehealthy. compared topriorphotographs.Thepatient’s motherdidn’t noticeanyotherlocalchangessuchastrauma,infectionorpain, Presentation Douglas Matsunaga, MD, KunalMalik, BA, andCarolL.Shields, MD EyeHospital. and treatmentatWills reflA yellowpupillary ex bringsa2-year-old boyinforconsultation

Examination underanesthesiarevealed On ocularexaminationatage2,uncorrect- The patientwasafraternaltwinbornat36weeksbycaesareansection.neonatalperiodcomplicatedneo- A 2-year-old boypresentedtotheophthalmologisttwoweeksafterhismothernoticedleftpupilappeared“cloudy” REVIEW Subretinal and (Figure 1Aand1B).Subretinal Wills Eye Wills Eye uid, and and uid, shows densedebrisunderthefovea andmildcystoid macularedema. angiography highlightsthetelangiectasiaandareas ofnon-perfusion.(D)OCT temporally. (B) A large macularcyst isseensuperiorly(arrows). (C)Fluorescein anesthesia shows densemacularexudation andextensive subtletelangiectasia Figure 1.(A)Fundusphotography ofthelefteye oninitialexamination under Resident CaseSeries Edited by Thomas Jenkins, MD February 2018 | reviewofophthalmology.com |

63 1/26/18 3:53 PM 063_rp0218_wills.indd 64 the presenceofextensiveretinaltelangiectasiaassociated nal fi brovascular tissueorvitreoretinalscarring.Instead, there wasanabsenceoftractionalelementsextrareti- the dilatedfundusexaminationwaslessconsistentas concern forlatesequelaeofretinopathyprematurity, tory ofprematuritywithNICUadmissionmightprompt betes mellitusandhypertension.Whilethepatient’s his- exudative retinopathy. Less-commoncausesincludedia- and someinfections.Rarelydoesretinoblastomadisplay retinopathy ofprematuritysequelae,retinitispigmentosa retinopathy, facioscapulohumeralmusculardystrophy, toma, vasoproliferativetumor, familialexudativevitreo- gies, includingCoats’disease,retinalhemangioblas- exudative retinopathyincludesawiderangeofpatholo- and tracecystoidmacularedema(Figure1D). dense, irregulardebriswithlossoftheouterretinallayers superiorly. OCTrevealedthefoveaoverlyingsubretinal bris andnocalcifi shallow retinaldetachmentwithsubretinaldensede- traction rior telangiectasiaandperipheralnon-perfusionwithout obtained. OnFA, thelefteyeshowedtemporalandinfe- ultrasonography andopticalcoherencetomographywere Workup, DiagnosisandTreatment 64 systemic diseases.Aone-year, prospectivesurveyinthe Coats’ israreandsporadic, hasn’t beenlinked toany retinal exudation,typicallyfoundinyoungmales. in 1908asunilateralretinalvascularabnormalitieswith Discussion photography atoneyear aftertreatment shows subfoveal glioticscar, temporal chorioretinal scarringandresolution ofthetelangiectasia. angiography duringthesamevisithighlightsresidual telangiectasiaadjacent tothechorioretinal scarringtemporally. (C) Fundus retinal exudation, chorioretinal andresidual scarringinareas telangiectasiaalongtheposteriormargin. ofcryotherapy (B)Fluorescein Figure 2.(A)Fundusphotography ofthelefteye fourmonthsafterfi demonstrates partialresolutionrst cryotherapy oftheregions of exudation withoutevidence ofvitreoretinaltraction. retinal telangiectasiawithintraretinaland/orsubretinal defi REVIEW The differentialdiagnosisina2-year-old patientwith Ancillary imagingwithfl uorescein angiography, ocular Coats’ diseasewasfirstdescribedbyGeorgeCoats | nition hassincebeenrefi ned tofi ReviewofOphthalmology Resident CaseSeries (Figure 1C).Ocularultrasonographydisclosed c mass.Therewasaretinalmacrocyst | February2018 ndings ofidiopathic 1 The 2,3 Coats’ diseaseincludeddecreased visualacuity, strabis- confi of theprevioustreatmenttemporally( and residualtelangiectasiaalongtheposteriormargin chorioretinal scarring,mildpersistentsubretinalfl 60-percent resolutionoftheexudation,withtemporal telangiectasia. laser photocoagulationandcryotherapytotheareasof Coats’ diseasewasestablishedandthepatientunderwent prior medicalorfamilyhistory, theclinicaldiagnosisof most suggestiveofCoats’disease.Giventheabsence with retinalexudation,nosignoftractionwas per 100,000. United Kingdomestimatedapopulationincidenceof0.09 was 5years(agerange:1month to63years). with unilateralfi disease, 76percentweremalesand95presented in youngermales:Inastudyof150patientswithCoats’ gliosis (Figure2C). giectasia andmacularexudation,withpersistentfoveal of treatmentshowedcompleteresolutionthetelan- most recentfollow-up12monthsafterthesecondround retina. Nofurtherinterventionwasperformed,andthe the foveadrapedoveroldexudationandanotherwisefl macular blockingdefectfromgliosis.OCTdemonstrated ment scarring.FA confirmed inactivetelangiectasiaanda with aresidualfovealglioticscarandperipheraltreat- ment, funduscopyrevealedminimalmacularexudation these remainingtelangiectasia. 2B). Asecondroundoftherapywasthenperformedover The mostcommoninitial presenting symptomsof On follow-upexaminationfourmonthslater, therewas On follow-upsixmonthsafterthesecondtreat- rmed thepresenceofresidualtelangiectasia 4 Thisconditiontypicallypresentsunilaterally ndings. Themedian ageatpresentation Figure 2A).FA 3 (Figure uid at 1/26/18 3:53 PM mus and leukocoria.3 In the natural tive retinal detachment is noted with in some cases of partial retinal de- course of the disease, retinal telangi- subclassifi cation detailing partial and tachment. In eyes with total retinal ectasia and associated vascular abnor- total retinal detachment as 3A and detachment, visual prognosis is con- malities, including microaneurysms, 3B, respectively. Stage 3A is further sidered poor11,14 and the decision arteriovenous communications and subclassifi ed into extrafoveal and fo- against intervention must be weighed capillary dropout lead to extensive veal partial detachment as 3A1 and against the risk of developing painful vascular leakage with subsequent 3A2, respectively. Stage 4 describes neovascular glaucoma. In two ret- subretinal fluid and exudation. In- eyes with total retinal detachment rospective case reviews of advanced terestingly, while most telangiectasia and secondary glaucoma. In stage 5, Coats’ disease that were untreated, are found temporally and anterior to end-stage disease has occurred with four of six and 18 of 25 patients pro- the macula, exudation is often found a blind, nonpainful or painful eye and gressed to neovascular glaucoma.14,15 more diffusely involving the periph- total retinal detachment. In a review Considering this risk, vitrectomy with ery and post-equatorial retina.3,5 Exu- of 124 eyes, the following incidenc- subretinal fl uid drainage, intravitreal dation in Coats’ disease is often re- es across stages were noted: stage 1 tamponade with silicone oil or gas, mote from the areas of telangiectasia (1-percent incidence); stage 2 (14 and concomitant cryotherapy or pho- and has a notable preference for the percent); stage 3 (68 percent); stage 4 tocoagulation to the telangiectasia macula, forming a macular star.2,3,5,6 (15 percent); and stage 5 (2 percent).2 has been performed with variable As subretinal fl uid progresses, retinal Recently, the subfoveal gliotic nodule success, with the goal of preventing detachment can occur and may prog- has been found to be predictive of development of painful neovascular ress to total detachment. macular fi brotic scarring and poorer glaucoma.2,12,13,16 Others have used Coats’ disease is primarily diag- visual outcomes.8 treatments such as intravitreal triam- nosed clinically, though several diag- The management of Coats’ dis- cinolone or repetitive laser photoco- nostic procedures can assist in un- ease is stage-dependent. Stage 1 or agulation directly to telangiectasia on clear cases. Fluorescein angiography early stage 2 disease with mild tel- the detached retina.17,18 Enucleation highlights telangiectasia with early angiectasias and only small amounts may be required in advanced disease hyperfl uorescence, hypofl uorescence of exudation are either observed or that has progressed to a blind painful of exudation, capillary dropout pe- treated with laser photocoagulation. eye with or without secondary glau- ripheral to telangiectasia, and mild Observation is especially considered coma. For stage 5 disease, in the ab- hyperfl uorescence of subretinal fl u- in older patients where the disease is sence of pain, observation is advised. id and overlying retinal capillaries. usually less aggressive. Also, sponta- The use of anti-VEGF has been Ultrasonography can be particularly neous regression of Coats’ disease has proposed as an adjunctive therapy for helpful in advanced cases with total been described.9,10 However, periodic Coats’ disease.11,19-22 VEGF has been exudative retinal detachment. Sub- follow-up should be maintained. In found to be elevated in the disease23 retinal fl uid will typically be clear or a retrospective study of 39 patients and a number of case series have de- with minor, noncalcific echogenici- across two decades, there was a trend scribed its use in Coats’ with favor- ty from subretinal cholesterolosis. toward better fi nal visual acuity in the able results.11,19,21,22,24 In one small These fi ndings are particularly help- second decade of life when eyes were series of 10 patients treated with in- ful in differentiating Coats’ from the treated more often and with a higher travitreal bevacizumab compared to solid mass with dense echoes of cal- number of procedures, suggesting 10 matched controls, all of the beva- cifi cation seen in retinoblastoma. In that a low threshold for treatment cizumab patients achieved full reso- unusual cases, cytological assessment is best.11 Appropriate treatment has lution of the disease, compared to of the subretinal fl uid can show lipid- been shown to anatomically stabilize eight out of 10 in the control group.20 laden macrophages and cholesterol or improve the eye in 76 percent of The effects of anti-VEGF therapy in crystals.3,7 eyes.2 Coats’ disease remains under study, The progression of Coats’ disease For stage 2 Coats’ disease, treat- and there are several limitations asso- has been classified into five stages. ment modalities include laser photo- ciated with it: One small study noted Stage 1 involves only retinal telangi- coagulation or cryotherapy directly to the formation of tractional fibrosis ectasias. Stage 2 includes additional the area of telangiectasia.2,12,13 Mul- (rarely seen in Coats’ disease) in four exudation, with further subclassifi- tiple treatments may be required, out of eight patients treated with in- cation specifying extrafoveal exuda- and areas of remote exudation of- travitreal bevacizumab.24 The use of tion as 2A and intrafoveal exudation ten resolve with the telangiectasia. anti-VEGF in the pediatric popula- as 2B. In stage 3, additional exuda- Both modalities may also be used tion may also be of concern, given

February 2018 | reviewofophthalmology.com | 65

0063_rp0218_wills.indd63_rp0218_wills.indd 6655 11/26/18/26/18 3:543:54 PMPM 0063_rp0218_wills.indd 66 6 3 _ r p 0 2 1 8 _ w elrIsrmns 5 Fax (610) Phone (800) Keeler Instruments 21 www.vision.abbott AMO) 15 Johnson &Vision (formerly 353-7814 523-5620 12 www.icare-usa.com Phone (888) Icare USA Fax (813) 2 Phone (800) Bausch +Lomb 389-4022 Fax (817) Phone (800) 7 Alcon Laboratories 975-7762 323-0000 www.akornconsumerhealth.com Phone (800) Akorn ConsumerHealth 551-4352 451-3937 (610)492-1028or [email protected] (610)492-1017or Michael Hoster 579-8327 [email protected] James Henne (610)492-1014or [email protected] Michele Barrett For advertisingopportunitiescontact: 66 to insert. due tospelling,incorrectpagenumber, orfailure correctly. Noallowancewillbemade forerrors contract. Everycarewillbetakentoindex 67, 68 25, 27 convenience andnotaspartoftheadvertising This advertiserindexispublishedasa www.shire.com Shire Ophthalmics Phone (888) S4OPTIK www.regeneron.com Phone (914) 17, 9 224-6012 Regeneron Pharmaceuticals, Inc. Fax (757) Phone (800) 847-7000 Lombart Instruments 855-1232 446-8092 18 i l l s

. REVIEW i n | d ReviewofOphthalmology Index Advertising d

6 6 | February2018 fl and failedresolutionofsubretinal the telangiectasia,retinalmacrocyst post-equatorial ordiffuselocationof Poor visualacuitywasassociatedwith stage 4andzeropercentof5. 2, 7percentofstage3,78 required in0percentofstages1and of stages4and5.Enucleationwas percent ofstage3and100 of stage1,53percent2,74 or worsewasfoundinzeropercent ment poorvisualacuityof20/200 study of124treatedeyes,post-treat- particularly stage-dependent.Ina trol ofthedisease. initially beentreatedwithgoodcon- out of86eyes(7percent)thathad of telangiectasiaandexudationinsix over 25years,therewasrecurrence In aretrospectiveanalysisperformed to notethatCoats’diseasecanrecur. strophic consequences. blastoma, leadingtopotentiallycata- a patientwithundiagnosedretino- is alsotheriskofmistakenlyinjecting small volumesofdistribution.There developing childrenwithrelatively the potentialforsystemiceffectsin cal features at diagnosis. at cal features Eye(Lond)2010;24:12:1797-1801. diseaseintheUnited KingdomI:Coats andclini- Epidemiology 4. MorrisB, Foot B, Mulvihill A. of study A population-based 2001;131:5:561-571. The 2000SanfordGiffordMemorialLecture. Am JOphthalmol diseasein150cases: ofCoats andcomplications variations 3. ShieldsJA, ShieldsCL, SG, Honavar Demirci H. Clinical Lecture. Am JOphthalmol2001;131:5:572-583. sifi disease: ofCoats andmanagement cation The 2000Proctor 2. ShieldsJA, ShieldsCL, SG, Honavar DemirciH, J. Cater Clas- 17:440-525. HospitalReports;1908: LondonOphthalmology Royal 1. G. Coats Forms ofretinaldiseaseswithmassiveexudation. vision. ing withleukocoriaand/ordecreased maintained insuchpatientspresent- a highindexofsuspicionshouldbe ents unilaterallyinyoungmales,and tion. Thisconditiontypicallypres- evidence ofretinalorvitrealtrac- with retinalexudationandwithout by idiopathicretinaltelangiectasia rare, nonhereditaryconditiondefi uid aftertreatment. The outcomeofCoats’diseaseis In conclusion,Coats’diseaseisa REVIEW Resident CaseSeries 2

2 It’s important 25

ned concern. J AAPOS. 2009;13:4:329-331. ophthalmology: intopediatric factor therapy Promise and 25. RL. Avery anti-vascularendothelialgrowth Extrapolating nal traction. BrJOphthalmol2012;96:3:356-359. retinaldetachmentandriskofvitreoreti- disease withexudative 24. Ramasubramanian A, ShieldsCL. BevacizumabforCoats’ Arch ClinExpOphthalmol2010;248:10:1519-1521. roleofbevacizumab.disease andpossibletherapeutic Graefes factorlevelinCoats’ vascularendothelialgrowth Elevated 23. He YG, Wang H, ZhaoB, LeeJ, BahlD, McCluskeyJ. Arch ClinExpOphthalmol2014;252:1:35-42. disease. forCoats’ injection astheinitialtreatment Graefes 22. ZhengXX, Jiang YR. bevacizumab The effectofintravitreal with laservascularablation. ClinOphthalmol2014;8:973-976. bevacizumabcombined withintravitreal diseasetreated Coats’ 21. VillegasVM,Gold AS,Berrocal AM,Murray TG. Advanced 2013;97:3:272-277. bevacizumab.disease withintravitreal BrJOphthalmol 20. RayR, BarañanoDE, HubbardGB. Treatment ofCoats’ Retina 2010;30:4:617-622. diseaseinchildren. ofCoats real bevacizumabinthetreatment 19. LinCJ, HwangJF, Chen YT, ChenSN. The effectofintravit- 649. disease.amcinolone inCoats’ 2012;119:3:648- Ophthalmology 18. GhaziNG, Al ShamsiH, LarssonJ, Abboud E. tri- Intravitreal disease. forCoats agulation Retina2016;36:7:1388-1394. 17. LevinsonJD, HubbardGB. laserphotoco- 577-nmyellow detachment. DocOphthalmol1995;90:4:387-394. retinal exudative Coats’-like Vitrectomy techniquesinlate-stage 16. Yoshizumi MO, Kreiger AE, LewisH, Foxman B, HakakhaBA. mic Surg1988;19:2:89-93. disease. ofadvancedCoats’ andmanagement Ophthal- history 15. SilodorSW, Augsburger JJ, ShieldsJA, Tasman W. Natural Soc 1991;89:371-476. 14. HaikBG. disease.Advanced Coats’ Trans Am Ophthalmol outcomes. Eye(Lond)2010;24:12:1802-1807. disease intheUnitedKingdomII: Investigation, treatment, and 13. Mulvihill A, MorrisB. ofCoats study A population-based Saunders, 2013:1058-1070. Disease. In: Schachat A, ed. Retina(Fifth Edition). London: W.B. 12. LondonNJS, ShieldsCL, HallerJA. 56-Coats Chapter 2017;124:9:1368-1376. Ophthalmology Disease:Visual OutcomesinCoats’ A 20-Year Experience. 11. OngSS, BuckleyEG, McCuenBW, etal. Comparisonof 2006;124:8:1208-1209. disease. inCoats’ subretinal exudate Arch Ophthalmol 10. Wolfe JD, HubbardGB. Spontaneousregressionof 1982;17:4:169-172. disease.sion ofretinallesionsinCoats’ CanJOphthalmol 9. Deutsch TA, RabbMF, JampolLM. Spontaneousregres- Predicting Visual Prognosis. Retina2017;37:8:1591-1598. disease:nodule inCoats’ Toward Classifi anUpdated cation 8. Daruich AL, Moulin AP, Tran HV, Matet A, MunierFL. Subfoveal phia: Wolters Kluwer;2017. 7. R. Eagle EyePathology: An Atlas and Text. Third ed. Philadel- 1387. ofmanagement.Evaluation 1982;89:12:1381- Ophthalmology 6. RidleyME, ShieldsJA, GC, Brown Tasman W. disease. Coats’ mol 1974;92:2:109-112. I,5.Egerer Tasman W, Tomer TT.disease.Ophthal- Arch Coats 11/26/18 3:54 PM / 2 6 / 1 8

3 : 5 4

P M VGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV the recommended human ophthalmic dose [RHOD], based on VJGCTGCWPFGTVJGEWTXG=#7%?NGXGN 5KPEGJWOCPU[UVGOKE GZRQUWTGVQNKƂVGITCUVHQNNQYKPIQEWNCTCFOKPKUVTCVKQPQH:KKFTC Rx Only CVVJG4*1&KUNQYVJGCRRNKECDKNKV[QHCPKOCNƂPFKPIUVQVJG risk of Xiidra use in humans during pregnancy is unclear. Animal Data BRIEF SUMMARY: .KƂVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU +8 KPLGEVKQP Consult the Full Prescribing Information for complete product VQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[ECWUGF information. an increase in mean preimplantation loss and an increased INDICATIONS AND USAGE KPEKFGPEGQHUGXGTCNOKPQTUMGNGVCNCPQOCNKGUCVOIMI Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJG FC[TGRTGUGPVKPIHQNFVJGJWOCPRNCUOCGZRQUWTGCV VTGCVOGPVQHVJGUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'&  the RHOD of Xiidra, based on AUC. No teratogenicity was QDUGTXGFKPVJGTCVCVOIMIFC[ HQNFVJGJWOCP DOSAGE AND ADMINISTRATION RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7% +PVJGTCDDKV Instill one drop of Xiidra twice daily (approximately 12 hours an increased incidence of omphalocele was observed at the CRCTV KPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT&KUECTF NQYGUVFQUGVGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOC VJGUKPINGWUGEQPVCKPGTKOOGFKCVGN[CHVGTWUKPIKPGCEJG[G GZRQUWTGCVVJG4*1&DCUGFQP#7% YJGPCFOKPKUVGTGFD[ Contact lenses should be removed prior to the administration +8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[UVJTQWIJ#HGVCN0Q QH:KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPI 1DUGTXGF#FXGTUG'HHGEV.GXGN 01#'. YCUPQVKFGPVKƂGFKP administration. the rabbit. CONTRAINDICATIONS Lactation 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKƂVGITCUVKPJWOCP Xiidra is contraindicated in patients with known hypersensitivity VQNKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVUKPVJG milk, the effects on the breastfed infant, or the effects on milk RTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKƂVGITCUVHTQO formulation. ocular administration is low. The developmental and health ADVERSE REACTIONS DGPGƂVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGFCNQPIYKVJ Clinical Trials Experience the mother’s clinical need for Xiidra and any potential adverse Because clinical studies are conducted under widely varying effects on the breastfed child from Xiidra. conditions, adverse reaction rates observed in clinical studies Pediatric Use of a drug cannot be directly compared to rates in the clinical 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH VTKCNUQHCPQVJGTFTWICPFOC[PQVTGƃGEVVJGTCVGUQDUGTXGF years have not been established. KPRTCEVKEG+PƂXGENKPKECNUVWFKGUQHFT[G[GFKUGCUGEQPFWEVGF YKVJNKƂVGITCUVQRJVJCNOKEUQNWVKQPRCVKGPVUTGEGKXGFCV Geriatric Use NGCUVFQUGQHNKƂVGITCUV QHYJKEJTGEGKXGFNKƂVGITCUV  No overall differences in safety or effectiveness have been 6JGOCLQTKV[QHRCVKGPVU  JCFŰOQPVJUQHVTGCVOGPV observed between elderly and younger adult patients. GZRQUWTGRCVKGPVUYGTGGZRQUGFVQNKƂVGITCUVHQT NONCLINICAL TOXICOLOGY approximately 12 months. The majority of the treated patients Carcinogenesis, Mutagenesis, Impairment of Fertility YGTGHGOCNG  6JGOQUVEQOOQPCFXGTUGTGCEVKQPU Carcinogenesis: Animal studies have not been conducted TGRQTVGFKPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQP VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKƂVGITCUV dysgeusia and reduced visual acuity. Other adverse reactions Mutagenesis: .KƂVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro TGRQTVGFKPVQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQP #OGUCUUC[.KƂVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo conjunctival hyperemia, eye irritation, headache, increased mouse micronucleus assay. In an in vitro chromosomal lacrimation, eye discharge, eye discomfort, eye pruritus and aberration assay using mammalian cells (Chinese sinusitis. JCOUVGTQXCT[EGNNU NKƂVGITCUVYCURQUKVKXGCVVJGJKIJGUV Postmarketing Experience concentration tested, without metabolic activation. 6JGHQNNQYKPICFXGTUGTGCEVKQPUJCXGDGGPKFGPVKƂGFFWTKPI Impairment of fertility: .KƂVGITCUVCFOKPKUVGTGFCV postapproval use of Xiidra. Because these reactions are KPVTCXGPQWU +8 FQUGUQHWRVQOIMIFC[ reported voluntarily from a population of uncertain size, it is not HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG always possible to reliably estimate their frequency or establish TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG 4*1& QH a causal relationship to drug exposure. NKƂVGITCUVQRJVJCNOKEUQNWVKQP JCFPQGHHGEVQP Rare cases of hypersensitivity, including anaphylactic reaction, fertility and reproductive performance in male and bronchospasm, respiratory distress, pharyngeal edema, swollen female treated rats. tongue, and urticaria have been reported. Eye swelling and rash have been reported. USE IN SPECIFIC POPULATIONS Pregnancy /CPWHCEVWTGFHQT5JKTG75+PE5JKTG9C[.GZKPIVQP/# There are no available data on Xiidra use in pregnant women to (QTOQTGKPHQTOCVKQPIQVQYYY:KKFTCEQOQTECNN KPHQTOCP[FTWICUUQEKCVGFTKUMU+PVTCXGPQWU +8 CFOKPKUVTCVKQP Marks designated ®CPFvCTGQYPGFD[5JKTGQTCPCHƂNKCVGFEQORCP[ QHNKƂVGITCUVVQRTGIPCPVTCVUHTQORTGOCVKPIVJTQWIJ 5JKTG75+PE5*+4'CPFVJG5JKTG.QIQCTGVTCFGOCTMUQT IGUVCVKQPFC[FKFPQVRTQFWEGVGTCVQIGPKEKV[CVENKPKECNN[ TGIKUVGTGFVTCFGOCTMUQH5JKTG2JCTOCEGWVKECN*QNFKPIU+TGNCPF relevant systemic exposures. Intravenous administration of .KOKVGFQTKVUCHƂNKCVGU NKƂVGITCUVVQRTGIPCPVTCDDKVUFWTKPIQTICPQIGPGUKURTQFWEGF Patented: please see JVVRUYYYUJKTGEQONGICNPQVKEGRTQFWEVRCVGPVU an increased incidence of omphalocele at the lowest dose .CUV/QFKƂGF5

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Indication Proven to treat the signs of inferior corneal Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJGVTGCVOGPV staining in 12 weeks and symptoms of eye of signs and symptoms of dry eye disease (DED). dryness in 12, 6, and as little as 2. Important Safety Information Xiidra is contraindicated in patients with known hypersensitivity Xiidra helped provide symptom relief from VQNKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVU eye dryness in some patients at week 2—and a measurable reduction in signs of inferior +PENKPKECNVTKCNUVJGOQUVEQOOQPCFXGTUGTGCEVKQPUTGRQTVGFKP corneal staining in just 12 weeks. Consider of patients were instillation site irritation, dysgeusia and reduced visual :KKFTCVQJGNR[QWT&T['[GRCVKGPVUƂPFVJG CEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKPVQQHVJGRCVKGPVUYGTG relief they’ve been waiting for. blurred vision, conjunctival hyperemia, eye irritation, headache, increased lacrimation, eye discharge, eye discomfort, eye pruritus and sinusitis. Check it out at Xiidra-ECP.com To avoid the potential for eye injury or contamination of the solution, patients should not touch the tip of the single-use container to their Four randomized, double-masked, 12-week trials GXCNWCVGFVJGGHƂECE[CPFUCHGV[QH:KKFTCXGTUWU eye or to any surface. vehicle as assessed by improvement in the signs Contact lenses should be removed prior to the administration of (measured by Inferior Corneal Staining Score) and symptoms (measured by Eye Dryness Score) of Dry :KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPICFOKPKUVTCVKQP Eye Disease (N=2133). 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH[GCTU have not been established.

For additional safety information, see accompanying Brief Summary of Safety Information on the adjacent page and Full Prescribing Information on Xiidra-ECP.com.

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